1,4-Diazacycloheptane series derivatives and preparation methods thereof

Abstract

The present invention relates to the field of organic synthesis, and in particular to a 1,4-diazepine derivative series and a preparation method thereof. A synthetic reaction is performed with reference to the following synthetic route: #imgabs0# wherein R is selected from an alkyl group or an aromatic group, R1, R2 and R3 are independently selected from hydrogen or an alkyl group, and Ar represents an aromatic group. The finished product prepared by the method has a low impurity content and stable quality indicators, and a 1,4-diazepine derivative series can be obtained.

Description

Technical Field

[0001] The present invention relates to the field of organic synthesis, and in particular to a series of 1,4-diazacycloheptane derivatives and a preparation method thereof. Background Art

[0002] The 1,4-diazepine structure appears in many APIs, such as Ripasudil (K-115), Fasudil and Suvorexant. The 1,4-diazepine structure has specific biological activity. The structural formulas of Ripasudil, Fasudil and Suvorexant are shown below:

[0003] .

[0004] Take Rosudild as an example. It is a Rho kinase (ROCK, Rho-associated coiled-coil kinase, Rho-related coiled-coil forming protein kinase) specific inhibitor, developed and sold by Kowa Pharmaceutical (Kowa) of Japan. It was approved by the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) on September 26, 2014, and is suitable for the second-line treatment of glaucoma and ocular hypertension. There are currently two main synthetic routes for Rosudild reported in the literature. One of the synthetic routes is:

[0005] , This route uses 4-fluoroisoquinoline-5-sulfonyl chloride as the starting material, and directly synthesizes a seven-membered ring on the substrate through a linear process to obtain rosudil. This synthetic route does not have protection and deprotection steps to directly obtain the product, and the steps are simple, which is feasible from the perspective of synthetic methodology. However, in actual production, the expensive 4-fluoroisoquinoline-5-sulfonyl chloride is directly used as the starting material of the route, resulting in a large loss of yield after multiple steps of reaction, and the final cost is high; secondly, the linear process is not conducive to impurity control and has poor anti-interference ability.

[0006] Another synthetic route is:

[0007] , This route uses a convergent process, first using S-2-amino-1-propanol as the starting material to synthesize a seven-membered ring intermediate, then condensing it with 4-fluoroisoquinoline-5-sulfonyl chloride and removing the Boc protection to obtain rosudil. Although this process has more steps than the original process, the materials used to prepare INT B are all low-cost, and they are combined with 4-fluoroisoquinoline-5-sulfonyl chloride at the end of the process, which reduces the loss of high-cost raw materials and effectively reduces costs. However, there are isomeric impurities in this process that are difficult to remove, as shown below:

[0008] . In addition, the process uses methylsulfonyl chloride, azodicarboxylic acid diester, etc. Methanesulfonyl chloride is a highly toxic substance, which is very dangerous and has limited use; azodicarboxylic acid diester is prone to explosion when heated or impacted, and is highly toxic; the atom economy is not high, and an equivalent amount of azodicarboxylic acid diester and triphenylphosphine are used; an equivalent amount of hydrazine dicarboxylic acid diester and triphenylphosphine oxide are generated, which are difficult to remove and form waste residues, especially triphenylphosphine oxide is extremely difficult to remove. It can be seen that the preparation method of 1,4-diazacycloheptane series derivatives has problems such as high impurity content and unstable quality indicators. Summary of the invention

[0009] The invention provides a 1,4-diazacycloheptane series derivative and a preparation method thereof, aiming to improve the problems in the existing process. The prepared finished product has low impurity content and stable quality indicators, and the 1,4-diazacycloheptane series derivative can be obtained.

[0010] The present invention is achieved in that:

[0011] In the first aspect, the present invention provides a method for preparing a series of 1,4-diazacycloheptane derivatives, and the synthesis reaction is carried out according to the following synthesis path.

[0012] , Wherein, R is selected from an alkyl group or an aromatic group, R1, R2 and R3 are independently selected from hydrogen or an alkyl group, and Ar represents an aromatic group.

[0013] Further, in a preferred embodiment of the present invention, R1, R2 and R3 are independently selected from hydrogen or C1-C6 alkyl;

[0014] Preferably, R1, R2 and R3 are independently selected from any one of hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, isobutyl and n-butyl;

[0015] Preferably, Ar represents any one of substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted anthracenyl, substituted or unsubstituted phenanthrenyl and substituted or unsubstituted biphenyl;

[0016] Preferably, Ar represents any one of phenyl, p-tolyl, m-tolyl, o-tolyl, p-nitrobenzene, p-xylyl, m-xylyl and o-xylyl;

[0017] Preferably, It represents any one of methanesulfonyl chloride, benzenesulfonyl chloride and p-toluenesulfonyl chloride.

[0018] Further, in a preferred embodiment of the present invention, the operation steps of step 1 include: mixing raw material 1, raw material 2, a first acid binding agent and a mixed solvent for reaction, wherein the structural formula of raw material 1 is: , the structural formula of raw material 2 is: ;

[0019] Preferably, the operation steps of step 1 include: mixing the raw material 1, the first acid binding agent and water to form a first mixed solution, and then cooling the mixture to 0-5°C;

[0020] Mixing the raw material 2 with the first organic solvent to form a second mixed solution;

[0021] Then, the first mixed solution and the second mixed solution are mixed at 0-5°C, and then reacted at 15-20°C.

[0022] Further, in a preferred embodiment of the present invention, the first acid binding agent is selected from carbonate or bicarbonate, preferably sodium bicarbonate;

[0023] Preferably, the molar ratio of the raw material 1 to the raw material 2 is 1:0.8-1.2, and the molar ratio of the raw material 1 to the first acid binding agent is 1:1.2-1.5.

[0024] Further, in a preferred embodiment of the present invention, the operation steps of step 2 include: mixing the intermediate 1, the raw material 3, the first catalyst, the second acid binding agent and the second organic solvent for reaction; wherein the structural formula of the raw material 3 is: ;

[0025] Preferably, the operation steps of step 2 include: mixing the intermediate 1, the first catalyst, the second acid binding agent and the second organic solvent, and then heating to 50-60° C. under an inert gas atmosphere, mixing with the raw material 3, and reacting completely at 50-60° C.

[0026] Further, in a preferred embodiment of the present invention, the first catalyst comprises an ammonium iodide compound, preferably tetrabutylammonium iodide;

[0027] Preferably, the second organic solvent is selected from formamide solvents, preferably N,N-dimethylformamide;

[0028] The second acid binding agent is selected from phosphates, preferably potassium phosphate;

[0029] Preferably, the molar ratio of the intermediate 1 to the second acid binding agent is 1:1.8-2.2, the molar ratio of the intermediate 1 to the first catalyst is 1:0.08-0.12; and the molar ratio of the intermediate 1 to the raw material 3 is 1:1.2-1.5.

[0030] Further, in a preferred embodiment of the present invention, the operation steps of step 3 include: intermediate 2, a third acid binding agent, , a second catalyst and a third solvent are mixed to react;

[0031] Preferably, the operation steps of step 3 include: mixing the intermediate 2, the third acid binding agent, the solvent, the second catalyst and the third solvent to form a third mixed liquid, and cooling the mixture to 0-5° C.;

[0032] Then with The mixture is mixed with the third solvent, and then the temperature is returned to 20-25° C. for reaction.

[0033] Further, in a preferred embodiment of the present invention, the third acid binding agent comprises an amine substance, preferably triethylamine;

[0034] Preferably, the second catalyst is a pyridine compound, preferably dimethylaminopyridine;

[0035] Preferably, the molar ratio of the intermediate 2 to the second catalyst is 1:0.08-0.12; the molar ratio of the intermediate 2 to the third acid binding agent is 1:2.5-3.5; The molar ratio is 1:2.0-2.5.

[0036] Further, in a preferred embodiment of the present invention, the operation steps of step 4 include: mixing the intermediate 3, ammonia water and the fourth solvent for reaction, and then reacting with hydrochloric acid to form a salt;

[0037] Preferably, the ammonia water is ammonia water with a concentration of 15-30%;

[0038] Preferably, the reaction temperature is 80-100°C.

[0039] In a second aspect, an embodiment of the present invention provides a 1,4-diazacycloheptane series derivative, which is prepared by the above-mentioned preparation method of the 1,4-diazacycloheptane series derivative.

[0040] The beneficial effects of the present invention are as follows: the present invention provides a new preparation process of 1,4-diazacycloheptane series derivatives, which can avoid the problems existing in the existing process, the product has low impurity content and high purity, stable quality indicators, and can prepare 1,4-diazacycloheptane intermediates with various substituents, and does not use highly toxic methylsulfonyl chloride, azodicarboxylic acid diesters, etc. The process is easy to operate, the raw materials are all conventional materials, and the raw material cost is low. At the same time, the intermediates of steps 2 and 3 in the preparation process provided by the embodiment of the present invention do not need to be purified and post-treated separately, and can be directly subjected to the next step of reaction, and crystallization and purification are not performed until the last step of the reaction is completed. Even so, a high-purity product can be obtained, which further illustrates that the preparation process provided by the embodiment of the present invention is simple to operate, has a high tolerance for impurities in the process of the intermediate, and is easy to industrialize. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings required for use in the embodiments will be briefly introduced below. It should be understood that the following drawings only show certain embodiments of the present invention and therefore should not be regarded as limiting the scope. For ordinary technicians in this field, other related drawings can be obtained based on these drawings without paying creative work.

[0042] Figure 1 is the H NMR spectrum of the product INTA provided in Embodiment 1 of the present invention;

[0043] Figure 2 It is the HPLC chart of the product INTA provided in Example 1 of the present invention. DETAILED DESCRIPTION

[0044] In order to make the purpose, technical scheme and advantages of the embodiments of the present invention clearer, the technical scheme in the embodiments of the present invention will be described clearly and completely below. If the specific conditions are not specified in the embodiments, they are carried out according to conventional conditions or conditions recommended by the manufacturer. If the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be purchased commercially.

[0045] The following is a detailed description of a series of 1,4-diazacycloheptane derivatives and a preparation method thereof according to an embodiment of the present invention.

[0046] The embodiment of the present invention provides a method for preparing a 1,4-diazacycloheptane series derivative. The structural formula of the 1,4-diazacycloheptane series derivative is as follows:

[0047] , wherein R1, R2 and R3 are independently selected from hydrogen or alkyl, such as C1-C6 alkyl, and specifically any one of methyl, ethyl, n-propyl, isopropyl, tert-butyl, isobutyl and n-butyl can be selected, but it can be understood that the above alkyl is only an example of the embodiment of the present invention, and alkyl such as n-pentyl and isopentyl can also be selected, or substituted alkyl such as benzyl, monochloromethyl, dichloromethyl can be selected.

[0048] Ar represents an aromatic group, which can be selected from any one of substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted anthracenyl, substituted or unsubstituted phenanthryl and substituted or unsubstituted biphenyl; specifically, it includes but is not limited to phenyl, p-tolyl, m-tolyl, o-tolyl, p-nitrobenzene, p-xylyl, m-xylyl and o-xylyl, and aromatic groups such as methyl substituted naphthyl can also be selected.

[0049] Specifically, the synthesis was carried out according to the following synthesis route:

[0050] , The specific process is as follows:

[0051] Step 1: Mix raw material 1, raw material 2, a first acid binding agent and a mixed solvent for reaction, wherein the structural formula of raw material 1 is: , the structural formula of raw material 2 is: Specifically, the raw material 1, the first acid binding agent and water are mixed to form a first mixed solution, and then the temperature is lowered to 0-5°C; the raw material 2 is mixed with the first organic solvent to form a second mixed solution; then, the first mixed solution and the second mixed solution are mixed at 0-5°C, and then reacted at 15-20°C, and the reaction is detected by HPLC. When the o-nitrobenzenesulfonyl chloride is controlled to be ≤1.0% in HPLC, the reaction is stopped, and then post-treatment is performed.

[0052] Specifically, the post-treatment includes adding water to the reaction bottle and stirring, then extracting with ethyl acetate, combining the organic phases, drying with anhydrous sodium sulfate, and then concentrating under reduced pressure, steaming with methyl tert-butyl ether for 4 times, then adding methyl tert-butyl ether and steaming with stirring, filtering and drying under reduced pressure to obtain a white to off-white solid.

[0053] Furthermore, the first acid binding agent is selected from carbonate or bicarbonate, preferably sodium bicarbonate; the molar ratio of the raw material 1 to the raw material 2 is 1:0.8-1.2, for example, 1:0.8, 1:0.9, 1:1, 1:1.1 and 1:1.2, etc., any value between 1:0.8-1.2; the molar ratio of the raw material 1 to the first acid binding agent is 1:1.2-1.5, for example, 1:1.2, 1:1.3, 1:1.4 and any value between 1:1.2-1.5.

[0054] Step 2: Mix the intermediate 1, the raw material 3, the first catalyst, the second acid-binding agent and the second organic solvent to react; wherein the structural formula of the raw material 3 is: Specifically, the intermediate 1, the first catalyst, the second acid-binding agent and the second organic solvent are mixed, and then heated to 50-60° C. under an inert gas atmosphere, mixed with the raw material 3, and reacted completely at 50-60° C.

[0055] HPLC controlled intermediate 1≤2.0%, qualified, add water to the reaction bottle, control the internal temperature at 15-25℃. Extract the reaction solution three times with ethyl acetate, combine the organic phases, wash with hydrochloric acid and saturated brine twice in sequence, and then dry with anhydrous sodium sulfate. Concentrate under high vacuum.

[0056] Furthermore, the first catalyst comprises an ammonium iodide compound, preferably tetrabutylammonium iodide; the second organic solvent is selected from formamide solvents, preferably N,N-dimethylformamide; and the second acid binding agent is selected from phosphates, preferably potassium phosphate. The molar ratio of the intermediate 1 to the second acid binding agent is 1:1.8-2.2, for example, any value between 1:1.8-2.2 such as 1:1.8, 1:1.9, 1:2.0, 1:2.1 and 1:2.2; the molar ratio of the intermediate 1 to the first catalyst is 1:0.08-0.12; for example, any value between 1:0.08, 1:0.09, 1:0.1, 1:0.11 and 1:0.12; the molar ratio of the intermediate 1 to the raw material 3 is 1:1.2-1.5, for example, any value between 1:1.2, 1:1.3, 1:1.4 and 1:1.2-1.5.

[0057] Step 3: Intermediate 2, the third acid binding agent, Specifically, the intermediate 2, the third acid-binding agent, the solvent, the second catalyst and the third solvent are mixed to form a third mixed solution, and the temperature is reduced to 0-5°C; and then The mixture is mixed with the third solvent, and then the temperature is returned to 20-25° C. for reaction.

[0058] HPLC intermediate 2≤1.0%. After qualified, hydrochloric acid was added dropwise into the reaction bottle with stirring, and the layers were separated. The organic phase was added into a three-necked flask, and then sodium carbonate aqueous solution was added. The mixture was stirred at room temperature, and the layers were separated. The organic phase was washed with saturated brine, and then dried over anhydrous sodium sulfate, and concentrated under reduced pressure.

[0059] Further, the third acid-binding agent includes an amine substance, preferably triethylamine; the second catalyst is a pyridine compound, preferably dimethylaminopyridine; the molar ratio of the intermediate 2 to the second catalyst is 1:0.08-0.12; for example, 1:0.08, 1:0.09, 1:0.1, 1:0.11 and 1:0.12, etc., any value between 1:0.08-0.12; the molar ratio of the intermediate 2 to the third acid-binding agent is 1:2.5-3.5; for example, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9, 1:3.0, 1:3.1, 1:3.2, 1:3.3, 1:3.4 and 1:3.5, etc., any value between 1:2.5-3.5; the intermediate 2 and The molar ratio is 1:2.0-2.5, for example, 1:2.0, 1:2.1, 1:2.2, 1:2.3, 1:2.4 and 1:2.5, etc., any value between 1:2.0-2.5.

[0060] It represents any one of methanesulfonyl chloride, benzenesulfonyl chloride and p-toluenesulfonyl chloride. Of course, it can be understood that as long as the above reaction can be carried out, other sulfonyl chloride compounds can also be selected.

[0061] Step 4: The intermediate 3, ammonia water and the fourth solvent are mixed to react, and then reacted with hydrochloric acid to form a salt; specifically, the intermediate 3 ammonia water and the fourth solvent are mixed and added to a pressure autoclave for reaction, and the intermediate 3 is controlled to be ≤1.0% by HPLC. After the control is qualified, the temperature is cooled to room temperature, saturated brine is added, and the mixture is extracted three times with ethyl acetate. The organic phases are combined, washed once with saturated brine, dried with anhydrous sodium sulfate, concentrated to a substantially free fraction, added with dichloromethane and water, and hydrogen chloride-ethyl acetate solution is added dropwise at 0-5°C with stirring, and the solution is stirred for 2 hours after the addition is completed, filtered, rinsed with pre-cooled dichloromethane, and the filter cake is dried under reduced pressure.

[0062] The following is a detailed description of the preparation method of a 1,4-diazacycloheptane series derivative provided by the present invention in conjunction with specific examples.

[0063] Example 1

[0064] This embodiment provides a method for preparing a series of 1,4-diazacycloheptane derivatives, wherein the structural formula of the 1,4-diazacycloheptane derivative is: The specific synthesis process is as follows:

[0065] S1 reacts according to the following synthetic route:

[0066] ;

[0067] Add 20.0g R-2-amino-1-propanol (SM1), 100ml water, and 33.6g sodium bicarbonate to a 500ml three-necked reaction bottle, stir and cool to 0-5℃. Dissolve 57.8g o-nitrobenzenesulfonyl chloride in 100ml tetrahydrofuran, control the reaction temperature at 0-5℃ and add it dropwise to the reaction bottle. After the dropwise addition, naturally return to 15-20℃ and stir overnight. HPLC control o-nitrobenzenesulfonyl chloride ≤1.0%, control qualified. Add 100ml water to the reaction bottle and stir for 1 hour. The reaction solution was extracted with ethyl acetate (200 ml once, 100 ml twice), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and steamed four times with 100 ml of methyl tert-butyl ether. 100 ml of methyl tert-butyl ether was added, stirred at 5-10°C for 4 hours, filtered, and dried under reduced pressure at 40°C to obtain 54.6 g of a white to off-white solid with a yield of 78.8% and a HPLC purity of 99.9%.

[0068] The characterization data of the product INT1 are as follows: 1 H-NMR (CDCl3) δ:1.14(3H,d,J=6.8Hz),1.85(1H,br s),3.47-3.66(3H,m),5.48(1H,d,J=6.8Hz),7.72-7.79(2H,m),7.86-7.92(1H,m),8.15-8.20(1H,m); LC-MS:261.0[M+H + ].

[0069] S2 reacts according to the following synthetic route:

[0070] ;

[0071] Add 20.0g INT1, 32.6g potassium phosphate, 2.64g tetrabutylammonium iodide, and 140ml N,N-dimethylformamide to a 1L three-necked reaction bottle, stir under nitrogen protection and heat to 55°C, and drop 16.0g 3-bromopropanol. After the drop is completed, stir at 55°C for 12 hours. HPLC control INT1≤2.0%, the control is qualified. Add 500ml water to the reaction bottle and control the internal temperature at 15-25°C. The reaction solution is extracted three times with 200ml ethyl acetate, the organic phases are combined, washed once with 100ml 1M hydrochloric acid, washed twice with 100ml saturated brine, and then dried with anhydrous sodium sulfate. Concentrate under high vacuum and reduced pressure to obtain 16.1g of dark red oily liquid, with a yield of 65.7% and an HPLC purity of 83.1%.

[0072] The characterization data of the product INT2 are as follows: LC-MS: 319.0 [M+H + ].

[0073] S3 reacts according to the following synthetic route:

[0074] ;

[0075] Add 16.1g INT2, 15.3g triethylamine, 0.6g 4-dimethylaminopyridine, and 80ml dichloromethane to a 500ml three-necked reaction bottle, and cool to 0℃ while stirring. Dissolve 21.2g p-toluenesulfonyl chloride in 80ml dichloromethane and add it dropwise to the reaction bottle, controlling the temperature to 0℃. After the dripping is completed, naturally warm up to 20-25℃ and stir overnight. HPLC control INT2≤1.0%, after the control is qualified, add 80ml 1M hydrochloric acid to the reaction bottle and stir for 30min. Layer, add the organic phase to a 500ml three-necked flask, add 80ml 1M sodium carbonate aqueous solution, and stir at room temperature for 1 hour. Layer, wash the organic phase with 80ml saturated brine, dry it with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 33.2g of yellow-brown syrupy liquid, with a yield of 105.0% and an HPLC purity of 85.2%.

[0076] The characterization data of the product INT3 are as follows: LC-MS: 626.9 [M+H + ].

[0077] S4 reacts according to the following synthetic route:

[0078] ;

[0079] 10g INT3, 100ml 25% ammonia water, and 100ml acetonitrile were added to the autoclave and reacted at 90℃ for 4 hours. HPLC controlled INT3≤1.0%. After the control was qualified, the temperature was lowered to room temperature, 100ml saturated brine was added, and 100ml, 50ml, and 50ml ethyl acetate were used for extraction three times. The organic phases were combined, washed once with 100ml saturated brine, dried with anhydrous sodium sulfate, and concentrated until there was basically no fraction. 30ml dichloromethane and 0.3g water were added, and 15.7ml 4M hydrogen chloride-ethyl acetate solution was added dropwise at 0-5℃ with stirring. After the addition, the mixture was stirred for 2 hours, filtered, rinsed with pre-cooled dichloromethane, and the filter cake was dried under reduced pressure at 40℃ to obtain 3.7g of light yellow solid, with HPLC purity of 99.8%, a yield of 65.5%, and a total process yield of 35.61%.

[0080] The characterization diagram of the product INTA is shown in Figure 1-Figure 2 ,in, Figure 1 is the H NMR spectrum, Figure 2 It is a HPLC spectrum, and the specific data are as follows: 1 H NMR(400MHz,D2O)δ:8.00(m,1H),7.86(m,3H),

[0081] 4.42(m,1H),3.86(m,1H),3.61(dd,J1=14Hz,J2=6Hz,1H),3.47(m,2H),3.16(m,2H),2.03(m,2H),1.05(d,J=8Hz,3H);LC-MS:299.9[M+H + ].

[0082] Example 2

[0083] This embodiment provides a method for preparing a series of 1,4-diazacycloheptane derivatives, wherein the structural formula of the 1,4-diazacycloheptane derivative is: The synthesis process is as follows: R-2-amino-1-propanol in the first step of Example 1 is replaced by S-2-amino-1-propanol, and other conditions remain unchanged. The product is obtained with a yield of 36.1% and a purity of 99.5%.

[0084] Example 3

[0085] This embodiment provides a method for preparing a series of 1,4-diazacycloheptane derivatives, wherein the structural formula of the 1,4-diazacycloheptane derivative is: The synthesis process is as follows: R-2-amino-1-propanol in the first step of Example 1 is replaced by 2-aminoethanol, and 3-bromo-1-propanol in the second step is replaced by 3-bromo-1-butanol, and other conditions remain unchanged. The product is obtained with a yield of 33.9% and a purity of 98.9%.

[0086] Example 4

[0087] This embodiment provides a method for preparing a series of 1,4-diazacycloheptane derivatives, wherein the structural formula of the 1,4-diazacycloheptane derivative is: The synthesis process is as follows: R-2-amino-1-propanol in the first step of Example 1 is replaced by 1-amino-2-propanol, and other conditions remain unchanged. The product is obtained with a yield of 37.8% and a purity of 99.3%.

[0088] Example 5

[0089] This embodiment provides a method for preparing a series of 1,4-diazacycloheptane derivatives, wherein the structural formula of the 1,4-diazacycloheptane derivative is: The synthesis process is as follows: R-2-amino-1-propanol in the first step of Example 1 is replaced by S-2-amino-1-propanol, and o-nitrobenzenesulfonyl chloride is replaced by 2,4-dinitrobenzenesulfonyl chloride, and other conditions remain unchanged. The product is obtained with a yield of 31.7% and a purity of 99.6%.

[0090] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for preparing a series of 1,4-diazepane derivatives, characterized in that: Refer to the following synthetic route for the synthetic reaction ， wherein R is selected from an aromatic group, R1, R2 and R3 are independently selected from hydrogen or a C1-C6 alkyl group, and Ar represents a substituted or unsubstituted phenyl group; The operation steps of step 2 include: mixing the intermediate 1, the first catalyst, the second acid binding agent and the second organic solvent, and then heating to 50-60° C. under an inert gas atmosphere, mixing with the raw material 3, and reacting completely at 50-60° C., wherein the structural formula of the raw material 3 is: ; The first catalyst is tetrabutylammonium iodide; the second acid binding agent is selected from potassium phosphate; The operation steps of step 3 include: mixing the intermediate 2, the third acid binding agent, the second catalyst and the third solvent to form a third mixed solution, and cooling the mixture to 0-5°C; and then and the mixture of the third solvent, and then returning the temperature to 20-25° C. for reaction; Wherein, the third acid binding agent is triethylamine, and the second catalyst is a pyridine compound; The operation steps of step 4 include: mixing the intermediate 3, ammonia water and the fourth solvent for reaction at a reaction temperature of 80-100° C., and then reacting with hydrochloric acid to form a salt.

2. The preparation method according to claim 1, characterized in that The operation steps of step 1 include: mixing raw material 1, a first acid binding agent and water to form a first mixed solution, and then cooling the mixture to 0-5°C; Mixing the raw material 2 with the first organic solvent to form a second mixed solution; Then, the first mixed solution and the second mixed solution are mixed at 0-5°C, and then reacted at 15-20°C; wherein the structural formula of raw material 1 is: , the structural formula of raw material 2 is: ; The first acid binding agent is selected from carbonate or bicarbonate.

3. The preparation method according to claim 1, characterized in that: R1, R2 and R3 are independently selected from any one of hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, isobutyl and n-butyl.

4. The preparation method according to claim 1, characterized in that: Ar represents any one of phenyl, p-tolyl, m-tolyl, o-tolyl, p-nitrobenzene, p-xylyl, m-xylyl and o-xylyl.

5. The preparation method according to claim 1, characterized in that: It represents any one of methanesulfonyl chloride, benzenesulfonyl chloride and p-toluenesulfonyl chloride.

6. The preparation method according to claim 2, characterized in that: The first acid binding agent is sodium bicarbonate.

7. The preparation method according to claim 2, characterized in that: The molar ratio of the raw material 1 to the raw material 2 is 1:0.8-1.2, and the molar ratio of the raw material 1 to the first acid binding agent is 1:1.2-1.

5.

8. The preparation method according to claim 1, characterized in that: The second organic solvent is selected from formamide solvents.

9. The preparation method according to claim 1, characterized in that: The second organic solvent is N,N-dimethylformamide.

10. The preparation method according to claim 1, characterized in that: The molar ratio of the intermediate 1 to the second acid binding agent is 1:1.8-2.2, the molar ratio of the intermediate 1 to the first catalyst is 1:0.08-0.12; the molar ratio of the intermediate 1 to the raw material 3 is 1:1.2-1.

5.

11. The preparation method according to claim 1, characterized in that: The second catalyst is dimethylaminopyridine.

12. The preparation method according to claim 1, characterized in that: The molar ratio of the intermediate 2 to the second catalyst is 1:0.08-0.12; the molar ratio of the intermediate 2 to the third acid binding agent is 1:2.5-3.5; The molar ratio is 1:2.0-2.

5.

13. The preparation method according to claim 1, characterized in that: The ammonia water has a concentration of 15-30%.

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