A method of preparing galcanezumab

Abstract

The application belongs to the technical field of organic synthesis and medicine preparation, and particularly relates to a preparation method of gleditside. The preparation method is shown as follows: the synthesis route of the preparation method is shortened from five-step reactions to three-step reactions, the noble metal palladium or a large amount of heavy metal nickel used as a catalyst in the prior art is eliminated, the use of a large amount of dangerous reagents such as sodium hydrogen is eliminated, the method is convenient to operate, environment-friendly, safe, has a higher total yield, has low raw material cost, and is suitable for large-scale production.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of organic synthesis and medicine preparation, and particularly relates to a preparation method of gedatolisib. BACKGROUND

[0002] Gedatolisib is a highly effective selective dual inhibitor of all class I PI3K / mTOR developed by Pfizer, USA. The US FDA has granted it a potential "first-in-class" PI3K / mTOR inhibitor breakthrough therapy designation for the treatment of HR-positive / HER2-negative metastatic breast cancer patients who have experienced disease progression after receiving CDK4 / 6 inhibitor and non-steroidal aromatase inhibitor therapy. The FDA has granted gedatolisib fast track designation as a potential treatment option. Its mechanism of action and pharmacokinetic characteristics have high differences. Compared with isomer-specific PI3K inhibitors or mTOR inhibitors, simultaneous inhibition of all four class I PI3K isomers and mTOR limits the development of potential drug resistance. According to the drug fusion cloud database, gedatolisib is currently in clinical phase III for metastatic breast cancer in the United States, and is a highly potential new anticancer drug.

[0003]

[0004] At present, the preparation methods of gedatolisib reported in the literature are as follows:

[0005] Route one:

[0006]

[0007] This route is to generate 2-chloro-4,6-dimorpholinyl-1,3,5-triazine (II) by SNAr substitution of triazamine (I) as a starting material with morpholine, and then the obtained intermediate II is subjected to Suzuki coupling with 4-aminobenzoic acid pinacol ester (III) to form the key intermediate 4-(4,6-dimorpholin-1,3,5-triazin-2-yl) aniline (IV). Then, the obtained intermediate IV is subjected to reaction with 4-isocyanatobenzoic acid methyl ester (V) to synthesize intermediate VI, and finally the hydrolysis and acylation of the ester are carried out to synthesize the target molecule gedatolisib.

[0008] Route two

[0009]

[0010] The route takes cyanoguanidine and p-nitrobenzonitrile as raw materials, first realizes the ring formation of s-triazine by KOH base catalysis to obtain the intermediate 6-(4-nitrophenyl)-1,3,5-triazine-2,4-diamine (3), then realizes the ring formation of morpholine ring with 2,2'-dichloroether (4) under the catalysis of sodium hydrogen to obtain the intermediate 4,4'-(6-(4-nitrophenyl)-1,3,5-triazine-2,4-diyl) dimorpholine (5), then reduces by Raney nickel to obtain 4-(4,6-dimorpholine-1,3,5-triazin-2-yl) aniline (6), then performs acylation reaction with phenyl chloroformate (7) to obtain the key intermediate phenyl (4-(4,6-dimorpholino-1,3,5-triazin-2-yl) phenyl) carbamate (8), and finally, under the catalysis of triethylamine, (4-aminophenyl) [4-(dimethylamino)-1-piperidyl] ketone (9) is used to synthesize the target molecule gedatolisib.

[0011] The starting raw material of the route is easy to obtain, but there are some obvious problems. First, a large amount (4.3 equivalents) of dangerous reagent sodium hydride is used in the second step, and the high-toxicity and irritating 2,2'-dichloroether (4) is used as the key raw material to construct the ring, and only a moderate yield is obtained; in the fifth step, DMF is used as the solvent for the condensation reaction, which may produce genotoxic impurities in the last step of the raw material, and the high temperature of the reaction produces by-products, and the yield is only 77%, the product purity is low, and it is not conducive to industrialization.

[0012] From the analysis of the above route, it can be seen that route one has obvious problems: first, the side chain 4-aminobenzene boronic acid pinacol ester (III) used in the second step of Suzuki coupling is not easy to obtain in the market, and the cost of customization is high, and the noble metal palladium catalyst used in this step makes the preparation cost of the intermediate 4-(4,6-dimorpholine-1,3,5-triazin-2-yl) aniline IV high, the reaction uses DMF as the solvent, needs to be carried out under reflux conditions for 24 hours, the reaction time is long, the reaction temperature is high, which leads to high energy consumption and low production efficiency, and the post-treatment adopts column chromatography for purification, which is not conducive to scale-up production. Second, the side chain 4-isocyanate benzene acid methyl ester (V) used in the third step is not easy to obtain in the market, and the cost of customization is high. Finally, the yield of the fifth step of condensation reaction is only 52%, and the total yield of the whole route is 32%.

[0013] The second step of route two uses a large amount (4.3 equivalents) of dangerous reagent sodium hydride, and uses the high-toxicity and irritating 2,2'-dichloroether (4) as the key raw material to construct the ring, only a moderate yield is obtained; in the fifth step, DMF is used as the solvent for the condensation reaction, which may produce genotoxic impurities in the last step of the raw material, and the high temperature of the reaction produces by-products, and the yield is only 77%, the product purity is low, and it is not conducive to industrialization. SUMMARY

[0014] The present application aims at the defects of the prior art, and provides a preparation method of gedatolisib.

[0015] The preparation method of the gedatolisib comprises the following steps:

[0016] 1) (4-aminophenyl) [4- (dimethylamino) -1-piperidinyl] methanone (V) is reacted with triphosgene under the action of a reaction solvent and a base to prepare an isocyanate intermediate (VI) ;

[0017] 2) 4- (4, 6-dimorpholin-1, 3, 5-triazin-2-yl) aniline (IV) is reacted with the isocyanate intermediate (VI) under alkaline conditions,

[0018] and gedatolisib is prepared.

[0019] In the step 1), the addition amount of (4-aminophenyl) [4- (dimethylamino) -1-piperidinyl] methanone (V) is 1.0-1.3 equivalents; and the addition amount of triphosgene is 0.25-0.40 equivalents.

[0020] Preferably, the addition amount of (4-aminophenyl) [4- (dimethylamino) -1-piperidinyl] methanone (V) is 1.1-1.2 equivalents; and the addition amount of triphosgene is 0.33 equivalents.

[0021] In the step 1), the reaction solvent is selected from anhydrous THF or DCM; the added base is one of triethylamine, dimethylisopropylamine, diisopropylamine, pyridine, N, N-diisopropyl ethylamine and other organic bases; and the temperature for dropping triphosgene solution is-10-0 ℃.

[0022] In the step 2), the reaction temperature is 20-30 ℃; and the addition amount of 4-dimethylaminopyridine (DMAP) is 0.0175-0.0666 equivalents.

[0023] Preferably, the addition amount of 4-dimethylaminopyridine (DMAP) is 0.0333 equivalents.

[0024] Preferably, the method further comprises the step 3) preparation of gedatolisib: a crystallization solvent is a mixed solvent system of an alcohol solvent (methanol, ethanol, isopropanol, tert-butanol and the like) and ethyl acetate or heptane; the heating temperature is 65-75 ℃, and the crystallization temperature is 20-30 ℃.

[0025] The preparation method of 4-(4,6-dimorpholin-1,3,5-triazin-2-yl)aniline (IV) is as follows: trichloro-1,3,5-triazine (I) is used as a starting material to prepare 2-chloro-4,6-dimorpholin-4-yl-1,3,5-triazine (II) under alkaline conditions; in the second step, the key intermediate is prepared by using the strategy of kumada coupling catalyzed by a trace amount of Fe3+ catalyst, 2-chloro-4,6-dimorpholin-4-yl-1,3,5-triazine (II) is dissolved in anhydrous tetrahydrofuran, and kumada coupling is carried out with a previously prepared Grignard reagent under the catalysis of trace Fe(acac)3 and inert gas protection to obtain 4-(4,6-dimorpholin-1,3,5-triazin-2-yl)aniline (IV).

[0026] The Fe3+ catalyst is iron tris(acetylacetonate) Fe(acac)3, and the inert gas is nitrogen or argon.

[0027] The preparation method of the application is described in detail below, and the reaction formula is as follows:

[0028]

[0029] In the first step, 2-chloro-4,6-dimorpholin-4-yl-1,3,5-triazine (II) is prepared by using trichloro-1,3,5-triazine (I) as a starting material and morpholine under alkaline conditions according to the reference method;

[0030] In the second step, 4-(4,6-dimorpholin-1,3,5-triazin-2-yl)aniline (IV) is prepared by using 2-chloro-4,6-dimorpholin-4-yl-1,3,5-triazine (II) as a raw material and carrying out kumada coupling with a previously prepared Grignard reagent (III) under the catalysis of trace Fe(acac)3;

[0031] The third step is to prepare gedatilise by using the intermediate 4-(4,6-dimorpholin-1,3,5-triazin-2-yl)aniline (IV) under alkaline conditions and the isocyanate intermediate (VI) prepared by previously preparing (4-aminophenyl)[4-(dimethylamino)-1-piperidyl]methanone (V) and triphosgene.

[0032] Specifically, the preparation method comprises the following steps:

[0033] Step 1, cyanuric chloride was dissolved in acetone solvent, 2.0-4.0 equivalents of organic base was added, 2.0-2.1 equivalents of morpholine in acetone solution was added at room temperature, stirring at room temperature for at least 2 hours, sampling HPLC detection of control, until the raw material cyanuric chloride was completely reacted, the reaction was completed, and the temperature was lowered to -5-5°C, deionized water was slowly added, and the temperature was controlled at -5-5°C, after the dropwise addition was completed, the stirring was continued for at least 1 hour, the filter cake obtained after filtration was washed with water first and then with acetone, and the obtained solid was vacuum dried, the yield of this step was 75-90%, and the purity could reach more than 99.5%.

[0034] Step 2, preparation of 4-(4,6-dimorpholin-1,3,5-triazin-2-yl)aniline (II), which is divided into the following two stages:

[0035] First stage, preparation of Grignard reagent: Grignard reagent was prepared with 4-bromo-N,N-bis(trimethylsilyl)aniline as the starting material; the Grignard reagent was prepared using active magnesium powder or magnesium strip, Mg (1.02-1.3 eq) and I2 (0.005-0.05 w) were added, anhydrous tetrahydrofuran was used as the solvent, stirring and heating to 50-70°C, continuing to stir for more than 1 hour, dropwise adding a portion (about 10% w / w) of 4-bromo-N,N-bis(trimethylsilyl)aniline in tetrahydrofuran, and judging the initiation by observing the foaming phenomenon and the color change of the system solution, after successful initiation, the temperature was controlled at 50-70°C, the remaining 4-bromo-N,N-bis(trimethylsilyl)aniline in tetrahydrofuran was added dropwise, and stirring was continued for at least 1 hour, and sampling detection was performed in the middle, until 4-bromo-N,N-bis(trimethylsilyl)aniline was completely reacted, the reaction system was cooled to 0-10°C, and was ready for use, the obtained Grignard reagent solution could be used directly for the next stage of Kumada coupling reaction without further treatment.

[0036] The second stage, the Kumada coupling: adding the product of step 1, 2-chloro-4, 6-dimorpholin-4-yl-1, 3, 5-triazine, in anhydrous tetrahydrofuran as a solvent, stirring until completely dissolved, adding Fe (acac) 3 (0.01w~0.05w) at room temperature, dropwise adding the Grignard reagent solution prepared in the first stage, controlling the dropwise adding temperature at 25~35℃, incubating and stirring for at least 2 hours, adding acetic acid aqueous solution or dilute hydrochloric acid aqueous solution after the reaction is complete, stirring at room temperature for at least 1 hour, standing and separating the layers, washing the organic layer with saturated sodium chloride solution, concentrating the obtained organic layer, adding ethanol for solvent replacement, slowly cooling to-5~5℃, stirring for at least 1 hour, filtering, washing the filter cake with an alcohol solvent such as methanol, ethanol or isopropanol, obtaining a wet product, vacuum drying to obtain a light yellow solid powder, the purity is ≥98.5%, and the yield is 86~91%. If the obtained product is darker in color or lower in purity, it can be treated by slurry or recrystallization with a mixed solvent of ethanol or isopropanol and heptane.

[0037] Further, the organic base added in step 1 is one of triethylamine, dimethylisopropylamine, diisopropylamine and N, N-diisopropyl ethylamine.

[0038] Further, the concentration of the dilute hydrochloric acid aqueous solution added after the second stage Kumada coupling reaction is complete is 5%~10%.

[0039] Further, when the color of the product obtained in the second stage is too dark, a mixed solvent of tetrahydrofuran, ethanol or isopropanol and heptane is used for slurry again.

[0040] The method for preparing 4-bromo-N, N-bis (trimethylsilyl) aniline can refer to CN104788480B.

[0041] The reaction processes of the above two stages need to be carried out in an inert gas such as nitrogen or argon under anhydrous conditions, and the total yield of the two steps is 75%~85%, and the HPLC purity of the obtained product can reach more than 98.5%.

[0042] Step 3, preparation of Gadalixi:

[0043] The (4-aminophenyl) [4-(dimethylamino)-1-piperidinyl]methanone (V) is dissolved in anhydrous THF, a base such as TEA or DIPEA is added, and the temperature is lowered to -10 to 0°C. A THF solution of triphosgene is slowly added dropwise to the above solution, the temperature of the dropwise addition is controlled to be <0°C, after the dropwise addition is completed, the solution is stirred at 0±5°C for 30 minutes or more, and sampling HPLC detection is performed until the remaining amount of the starting material is <1%. After the reaction is completed, a THF solution of 4-(4,6-dimorpholin-1,3,5-triazin-2-yl)phenylamine (II) is added to the solution of the isocyanate (VI), a catalytic amount of DMAP is added, and the temperature is raised to room temperature and stirred for 3 hours or more. The solid product gradually precipitates, sampling HPLC detection is performed until the remaining amount of the starting material 4-(4,6-dimorpholin-1,3,5-triazin-2-yl)phenylamine II is <2%, and the target product is obtained in the form of a crude product after filtration, washing of the filter cake with deionized water, and then washing with THF.

[0044] The crude product is added to a mixed solvent of ethyl acetate / ethanol, heated to 65 to 75°C, stirred for at least 1 hour, cooled to room temperature, and stirred for 1 hour or more. Filtration is performed, the filter cake is washed with THF and then with ethanol, and a white solid wet product is obtained. The product is dried under reduced pressure at a temperature of 50°C or less to obtain gleditschide, which has a purity of 98.5% or more and a yield of 85% or more.

[0045] Further, the recrystallization solvent is selected from a mixed solvent system of an alcohol solvent (such as methanol, ethanol, isopropanol, tert-butanol, and the like) and ethyl acetate or heptane, and the stirring temperature is 65 to 75°C; and the crystallization temperature is 20 to 30°C.

[0046] The present application, the first step is to prepare 2-chloro-4,6-dimorpholin-4-yl-1,3,5-triazine (II) by using 3,5,6-trichloro-1,2,4-triazine (I) as starting material and morpholine under alkaline conditions; the second step is to prepare 4-(4,6-dimorpholin-1,3,5-triazin-2-yl) aniline (IV) by using the strategy of kumada coupling catalyzed by trace Fe(acac)3, dissolving 2-chloro-4,6-dimorpholin-4-yl-1,3,5-triazine (II) in anhydrous tetrahydrofuran, and carrying out kumada coupling with the previously prepared Grignard reagent (III) under the catalysis of trace Fe(acac)3 and the protection of inert gas such as nitrogen, argon, etc.; the third step is the key asymmetric urea synthesis step, which is to prepare the target product Gidalizil by reacting 4-(4,6-dimorpholin-1,3,5-triazin-2-yl) aniline (IV) with the isocyanate intermediate VI prepared by (4-aminophenyl)[4-(dimethylamino)-1-piperidinyl]methanone (V) and triphosgene under alkaline conditions. The synthesis route of the preparation method is shortened from five steps to three steps, which not only eliminates the use of noble metal palladium or a large amount of heavy metal nickel as catalyst in the prior art, but also eliminates the use of a large amount of dangerous reagents such as sodium hydride, is easy to operate, environment-friendly, safe, has a high total yield, has a low raw material cost, and is suitable for large-scale production.

[0047] The present application has the following advantages:

[0048] In the coupling step of the second step of the present application, the strategy of kumada coupling catalyzed by trace Fe(acac)3 is used to prepare the key intermediate 4-(4,6-dimorpholin-1,3,5-triazin-2-yl) aniline IV at a high yield, and the reaction conditions are mild and the noble metal palladium catalyst used in the Suzuki coupling in the prior art is eliminated, so that the development of a palladium removal process is not needed in the subsequent step, which will significantly reduce the raw material cost of the intermediate IV.

[0049] The third step, which is the key step of the present application, is the synthesis method of asymmetric urea, in which the raw material (4-aminophenyl)[4-(dimethylamino)-1-piperidinyl]methanone (V) for preparing the side chain is reacted with triphosgene under alkaline conditions to generate the isocyanate intermediate (VI) which is directly used in the next step without further separation, and then the key intermediate 4-(4,6-dimorpholin-1,3,5-triazin-2-yl) aniline (IV) is continuously reacted under alkaline conditions to generate the target product Gidalizil. The reaction is a classical preparation method of asymmetric urea, and has mild reaction conditions, simple operation and high yield. Phosgene and diphosgene are also suitable for the present method, but considering the safety and convenience of use, the present application preferably uses solid triphosgene. DETAILED DESCRIPTION

[0050] The following description is merely exemplary of the present application and is not intended to limit the application since modifications will undoubtedly be made which are fairly within the spirit of the application and the scope of equivalents thereof. What is claimed is:

[0051] Example 1: Preparation of 2-chloro-4,6-dimorpholinyl-1,3,5-triazine (II)

[0052] Into 1500 mL of acetone, 300 g of cyanuric chloride was dissolved, 462.6 g of N,N-diisopropylethylamine (2.2 eq) was added into the acetone solution, the previously prepared morpholine acetone solution (containing 283.5 g of morpholine, 2.0 eq) was slowly added into the acetone solution, stirring at room temperature for at least 2 hours, sampling HPLC control until the cyanuric chloride reaction was complete, the reaction solution was cooled to -5-5°C, 10% hydrochloric acid aqueous solution was added, the temperature was controlled at -5-5°C, after the dropwise addition was completed, stirring was continued for 1 hour, the filter cake obtained after filtration was washed with water first, then with methanol, the obtained solid was vacuum dried to obtain 417 g of solid, purity 99.6%, yield 89.7%.

[0053] Example 2: Preparation of 4-(4,6-dimorpholin-1,3,5-triazin-2-yl)aniline (IV)

[0054] First stage: preparation of Grignard reagent: 30 mL of anhydrous tetrahydrofuran was added to the reaction bottle, 4.6 g of active magnesium powder (1.1 eq) was added to the reaction bottle, 0.5 g of I2 was added, nitrogen was replaced, the temperature was raised to slight reflux, 4-bromo-N,N-bis(trimethylsilyl)aniline tetrahydrofuran solution (50 mL solution containing 5.4 g of 4-bromo-N,N-bis(trimethylsilyl)aniline) was added to the reaction bottle, and the reaction system gradually changed from light yellow to dark brown with foaming, indicating that the initiation was successful, the previously prepared 4-bromo-N,N-bis(trimethylsilyl)aniline tetrahydrofuran solution (250 mL containing 50 g of 4-bromo-N,N-bis(trimethylsilyl)aniline) was slowly added to the reaction system, the dropwise addition temperature was controlled, after the addition was completed, stirring was continued for at least 1 h, sampling detection of 4-bromo-N,N-bis(trimethylsilyl)aniline reaction safety, cooling to -5-5°C, directly used for the next stage of kumada coupling.

[0055] Stage 2: Kumada coupling: Add 1000 mL of anhydrous THF to a reaction flask, cool to room temperature, and add 0.5 g of Fe(acac)3 until dissolved. Add 50 g of 2-chloro-4,6-dimorpholinyl-1,3,5-triazine prepared in Stage 1 to the reaction system, and replace with nitrogen gas while stirring until the solution is clear. At room temperature, add the Grignard reagent solution prepared in Stage 1 dropwise to the reaction flask, controlling the temperature to be between 20-30°C. After the addition is complete, stir for 2 hours, and take samples for testing until the reaction is complete. Slowly add 50 mL of water to the reaction system to quench the reaction, and continue stirring at room temperature for 1 hour. Allow the mixture to separate into layers, wash the organic layer with saturated sodium chloride solution, allow the mixture to separate into layers again, add 10% hydrochloric acid solution to the organic layer, stir at room temperature for 1 hour, allow the mixture to separate into layers, and concentrate the organic layer until no liquid is flowing. Add 250 mL of ethanol, continue to concentrate until no liquid is flowing, add a mixture of 300 mL of ethanol and 100 mL of water, heat to 70-80°C, stir for 1 hour, then slowly cool to -5-5°C, stir for 1 hour, filter, add 150 mL of a mixture of ethanol and heptane (50 mL of ethanol: 100 mL of heptane) to the filter cake, and stir to form a slurry. Filter, wash with water and ethanol, and dry to obtain 51.5 g of the product, with a yield of 86% and a purity of 99.6%.

[0056] Example 3: Preparation of Galidesivir

[0057] Dissolve (4-aminophenyl)[4-(dimethylamino)-1-piperidinyl]methanone (74.2 g, 0.3 mol) in 200 mL of anhydrous THF to obtain solution A. Add triethylamine (60.7 g, 0.6 mol) to solution A, and cool to -10-0°C. Slowly add solution B (29.7 g of triphosgene dissolved in 50 mL of anhydrous THF) to the reaction system, controlling the temperature to be <0°C. After the addition is complete, stir at 0±5°C for 60 min, take samples for HPLC testing, and continue until the remaining raw material is <1%. Dissolve 4-(4,6-dimorpholin-1,3,5-triazin-2-yl)aniline (102.7 g, 0.3 mol) in 200 mL of anhydrous THF to obtain solution C. Add solution C to solution A, add 4-dimethylaminopyridine (DMAP, 1.2 g, 0.01 mol), heat to 20-30°C, and stir for 3 hours. Take samples for HPLC testing, and continue until the remaining raw material is <2%. Directly filter the mixture, wash the filter cake with 100 mL of deionized water, and then wash with 200 mL of THF to obtain crude galidesivir.

[0058] The obtained crude product was added to 150 mL of ethyl acetate / ethanol mixed solvent (v:v = 1 :2), heated to 65-75 °C, stirred for 2 hours, cooled to 20-30 °C, continued to stir for 1 hour, filtered, the filter cake was first washed with 100 mL of THF, then washed with 100 mL of ethanol, to obtain white solid wet product, the obtained wet product was dried at 40-50 °C under reduced pressure for 10 hours to obtain Gleditside 158.6 g, purity 98.5%, yield 85.9%.

[0059] Example 4: Preparation of Gleditside

[0060] (4-Aminophenyl)[4-(dimethylamino)-1-piperidinyl]methanone (81.6 g, 0.33 mol) was dissolved in 200 mL of anhydrous THF to obtain solution A, triethylamine (60.7 g, 0.6 mol) was added to solution A, cooled to -10-0 °C, and solution B of triphosgene in THF (29.7 g of triphosgene was dissolved in 50 mL of anhydrous THF to prepare solution B) was slowly added dropwise to the reaction system, the temperature was controlled to be <0 °C during the dropwise addition, after the dropwise addition was completed, it was stirred at 0±5 °C for 60 min, and sampling was performed for HPLC detection until the remaining raw material was <1%. 4-(4,6-Dimorpholin-1,3,5-triazin-2-yl)aniline (102.7 g, 0.3 mol) was dissolved in 200 mL of anhydrous THF to prepare solution C, solution C was added to solution A, 4-dimethylaminopyridine (DMAP, 1.2 g, 0.01 mol) was added, the temperature was raised to 20-30 °C, and stirred for 3 hours, sampling was performed for HPLC detection until the remaining raw material was <2%, and then directly filtered, the obtained filter cake was first washed with 100 mL of deionized water, then washed with 200 mL of THF to obtain crude Gleditside.

[0061] The obtained crude product was added to 150 mL of ethyl acetate / ethanol mixed solvent (v:v = 1 :2), heated to 65-75 °C, stirred for 2 hours, cooled to 20-30 °C, continued to stir for 1 hour, filtered, the filter cake was first washed with 100 mL of THF, then washed with 100 mL of ethanol, to obtain white solid wet product, the obtained wet product was dried at 40-50 °C under reduced pressure for 10 hours to obtain Gleditside 158.6 g, purity 98.5%, yield 85.9%.

[0062] Example 5: Preparation of Gleditside

[0063] (4-Aminophenyl)[4-(dimethylamino)-1-piperidinyl]methanone (89 g, 0.36 mol) was dissolved in 200 mL of anhydrous THF to obtain solution A, triethylamine (60.7 g, 0.6 mol) was added to solution A, and the temperature was lowered to -10-0 °C, and solution B of triphosgene in THF (29.7 g of triphosgene dissolved in 50 mL of anhydrous THF) was slowly added dropwise to the reaction system, and the temperature was controlled to be <0 °C during the dropwise addition, and after the dropwise addition was completed, the mixture was stirred at 0±5 °C for 60 min, and a sample was taken for HPLC detection until the residual raw material was <1%. 4-(4,6-Dimorpholin-1,3,5-triazin-2-yl)aniline (102.7 g, 0.3 mol) was dissolved in 200 mL of anhydrous THF to obtain solution C, and solution C was added to solution A, 4-dimethylaminopyridine (DMAP, 1.2 g, 0.01 mol) was added, the temperature was raised to 20-30 °C, and the mixture was stirred for 3 h, a sample was taken for HPLC detection until the residual raw material was <2%, and the mixture was directly filtered, and the obtained filter cake was first washed with 100 mL of deionized water, and then washed with 200 mL of THF to obtain crude gleditsaid.

[0064] The obtained crude product was added to 150 mL of a mixed solvent of ethyl acetate / ethanol (v:v=1:2), heated to 65-75 °C, stirred for 2 h, cooled to 20-30 °C, and stirred for another 1 h, filtered, and the filter cake was first washed with 100 mL of THF, and then washed with 100 mL of ethanol to obtain a white solid wet product, and the obtained wet product was dried at 40-50 °C under reduced pressure for 10 h to obtain gleditsaid 160.9 g, with a purity of 98.7% and a yield of 87.1%.

[0065] Example 6: Preparation of gleditsaid

[0066] Dissolve (4-aminophenyl)[4-(dimethylamino)-1-piperidinyl]methanone (96.5 g, 0.39 mol) in 200 mL of anhydrous THF to obtain solution A, add triethylamine (60.7 g, 0.6 mol) to solution A, cool to -10-0 °C, slowly drop solution B (29.7 g of triphosgene dissolved in 50 mL of anhydrous THF) into the reaction system, control the dropping temperature <0 °C, after dropping, stir at 0±5 °C for 60 min, take samples for HPLC detection until the residual raw material is <1%. Dissolve 4-(4,6-dimorpholin-1,3,5-triazin-2-yl)aniline (102.7 g, 0.3 mol) in 200 mL of anhydrous THF to obtain solution C, add solution C to solution A, add 4-dimethylaminopyridine (DMAP, 1.2 g, 0.01 mol), warm to 20-30 °C, stir for 3 h, take samples for HPLC detection until the residual raw material is <2%, directly filter, wash the obtained filter cake with 100 mL of deionized water first, then with 200 mL of THF to obtain the crude gleditsaid.

[0067] Add the obtained crude product to 150 mL of an ethyl acetate / ethanol mixed solvent (v:v=1:2), heat to 65-75 °C, stir for 2 h, cool to 20-30 °C, continue to stir for 1 h, filter, wash the filter cake with 100 mL of THF first, then with 100 mL of ethanol to obtain a white solid wet product, dry the obtained wet product at 40-50 °C under reduced pressure for 10 h to obtain gleditsaid 160.5 g, purity 98.2%, yield 86.9%.

[0068] Table 1: Experimental results using different amounts of (4-aminophenyl)[4-(dimethylamino)-1-piperidinyl]methanone

[0069]

[0070] As can be seen from Table 1, the amount of (4-aminophenyl)[4-(dimethylamino)-1-piperidinyl]methanone added has a certain effect on the yield of the product, but it does not need to be greatly excessive, and from the cost point of view, 1.1-1.2 equivalents can be preferred.

[0071] Example 7: Preparation of gleditsaid

[0072] (4-Aminophenyl)[4-(dimethylamino)-1-piperidinyl]methanone (74.2 g, 0.3 mol) was dissolved in 200 mL of anhydrous THF to obtain solution A, N,N-diisopropylethylamine (77.5 g, 0.6 mol) was added to solution A, and the temperature was lowered to -10-0 °C, and solution B of triphosgene in THF (29.7 g of triphosgene dissolved in 50 mL of anhydrous THF) was slowly added dropwise to the reaction system, and the temperature was controlled to be <0 °C during the dropwise addition, and after the dropwise addition was completed, the mixture was stirred at 0±5 °C for 60 min, and a sample was taken for HPLC detection until the residual raw material was <1%. 4-(4,6-Dimorpholin-1,3,5-triazin-2-yl)aniline (102.7 g, 0.3 mol) was dissolved in 200 mL of anhydrous THF to obtain solution C, and solution C was added to solution A, 4-dimethylaminopyridine (DMAP, 1.2 g, 0.01 mol) was added, the temperature was raised to 20-30 °C, and the mixture was stirred for 3 h, a sample was taken for HPLC detection until the residual raw material was <2%, and the mixture was directly filtered, and the obtained filter cake was first washed with 100 mL of deionized water, and then washed with 200 mL of THF to obtain crude gleditsaid.

[0073] The obtained crude product was added to 150 mL of a mixed solvent of ethyl acetate / ethanol (v:v=1:2), heated to 65-75 °C, stirred for 2 h, cooled to 20-30 °C, and stirred for another 1 h, filtered, and the filter cake was first washed with 100 mL of THF, and then washed with 100 mL of ethanol to obtain a white solid wet product, and the obtained wet product was dried at 40-50 °C under reduced pressure for 10 h to obtain gleditsaid 148.3 g, with a purity of 98.1% and a yield of 80.3%.

[0074] Example 8: Preparation of gleditsaid

[0075] (4-Aminophenyl)[4-(dimethylamino)-1-piperidinyl]methanone (74.2 g, 0.3 mol) was dissolved in 200 mL of anhydrous THF to obtain solution A, triethylamine (36.4 g, 0.36 mol) was added to solution A, and the temperature was lowered to -10-0 °C. Solution B of triphosgene in THF (29.7 g of triphosgene dissolved in 50 mL of anhydrous THF) was slowly added dropwise to the reaction system, and the temperature was controlled to be <0 °C. After the addition was completed, the mixture was stirred at 0±5 °C for 60 min. Sampling and HPLC detection showed that the reaction was incomplete, and 5% of the raw material remained. Solution C was prepared by dissolving 4-(4,6-dimorpholin-1,3,5-triazin-2-yl)aniline (102.7 g, 0.3 mol) in 200 mL of anhydrous THF, and solution C was added to solution A. 4-Dimethylaminopyridine (DMAP, 1.2 g, 0.01 mol) was added, and the temperature was raised to 20-30 °C. The mixture was stirred for 3 h, and sampling and HPLC detection showed that about 6% of the raw material remained. The mixture was directly filtered, and the obtained filter cake was first washed with 100 mL of deionized water and then washed with 200 mL of THF to obtain crude gleditsaid.

[0076] The obtained crude product was added to 150 mL of a mixture of ethyl acetate / ethanol (v:v=1:2), heated to 65-75 °C, and stirred for 2 h. The temperature was lowered to 20-30 °C, and the stirring was continued for 1 h. Filtration was performed, and the filter cake was first washed with 100 mL of THF and then washed with 100 mL of ethanol to obtain a white solid wet product. The obtained wet product was dried at 40-50 °C under reduced pressure for 10 h to obtain gleditsaid 130.2 g, with a purity of 97.8% and a yield of 70.5%.

[0077] Example 9: Preparation of gleditsaid

[0078] (4-Aminophenyl)[4-(dimethylamino)-1-piperidinyl]methanone (74.2 g, 0.3 mol) was dissolved in 200 mL of anhydrous THF to obtain solution A, triethylamine (45.5 g, 0.45 mol) was added to solution A, and the temperature was lowered to -10-0 °C. Solution B of triphosgene in THF (29.7 g of triphosgene dissolved in 50 mL of anhydrous THF) was slowly added dropwise to the reaction system, and the temperature was controlled to be <0 °C. After the addition was completed, the mixture was stirred at 0±5 °C for 60 min. Sampling and HPLC detection showed that the reaction was incomplete, and the reaction time was further extended to 120 min. The remaining 2% of the raw material was still present. Solution C was prepared by dissolving 4-(4,6-dimorpholin-1,3,5-triazin-2-yl)aniline (102.7 g, 0.3 mol) in 200 mL of anhydrous THF, and solution C was added to solution A. 4-Dimethylaminopyridine (DMAP, 1.2 g, 0.01 mol) was added, and the temperature was raised to 20-30 °C. The mixture was stirred for 3 h, and sampling and HPLC detection showed that about 3% of the raw material remained. The mixture was directly filtered, and the obtained filter cake was first washed with 100 mL of deionized water and then washed with 200 mL of THF to obtain crude gleditsaid.

[0079] The obtained crude product was added to 150 mL of a mixed solvent of ethyl acetate / ethanol (v:v=1:2), heated to 65-75 °C, and stirred for 2 h. The temperature was lowered to 20-30 °C, and the stirring was continued for 1 h. Filtration was performed, and the filter cake was first washed with 100 mL of THF and then washed with 100 mL of ethanol to obtain a white solid wet product. The obtained wet product was dried at 40-50 °C under reduced pressure for 10 h to obtain gleditsaid 145.5 g, with a purity of 98.1% and a yield of 78.8%.

[0080] Example 10: Preparation of gleditsaid

[0081] (4-Aminophenyl)[4-(dimethylamino)-1-piperidinyl]methanone (74.2 g, 0.3 mol) was dissolved in 200 mL of anhydrous THF to obtain solution A, triethylamine (75.9 g, 0.75 mol) was added to solution A, and the temperature was lowered to -10-0 °C, and solution B of triphosgene in THF (29.7 g of triphosgene dissolved in 50 mL of anhydrous THF to prepare solution B) was slowly added dropwise to the reaction system, and the temperature was controlled to be <0 °C during the dropwise addition, and after the dropwise addition was completed, the mixture was stirred at 0±5 °C for 60 min, and a sample was taken for HPLC detection, and the reaction was incomplete, and the reaction time was further extended to 120 min, and 2% of the raw material remained. 4-(4,6-Dimorpholin-1,3,5-triazin-2-yl)aniline (102.7 g, 0.3 mol) was dissolved in 200 mL of anhydrous THF to prepare solution C, and solution C was added to solution A, 4-dimethylaminopyridine (DMAP, 1.2 g, 0.01 mol) was added, the temperature was raised to 20-30 °C, and the mixture was stirred for 3 h, a sample was taken for HPLC detection, and the raw material remained about 3%, and the mixture was directly filtered, and the obtained filter cake was first washed with 100 mL of deionized water, and then washed with 200 mL of THF to obtain the crude gleditside.

[0082] The obtained crude product was added to 150 mL of a mixed solvent of ethyl acetate / ethanol (v:v=1:2), heated to 65-75 °C, stirred for 2 h, cooled to 20-30 °C, and stirred for another 1 h, filtered, and the filter cake was first washed with 100 mL of THF, and then washed with 100 mL of ethanol to obtain a white solid wet product, and the obtained wet product was dried at 40-50 °C under reduced pressure for 10 h to obtain gleditside 158.1 g, purity 98.7%, yield 85.6%

[0083] Table 2. Experimental results of different amounts of bases

[0084] Example Base type Base amount (equivalents) Yield (%) Purity (%) 3 Triethylamine 2.0 85.9 98.5 7 N,N-diisopropylethylamine 2.0 80.3 98.1 8 Triethylamine 1.2 70.5 97.8 9 Triethylamine 1.5 78.8 98.1 10 Triethylamine Triethylamine 2.5 85.6 98.7

[0085] As can be seen from Table 2 above, different types of bases and the amount of base have a significant effect on the reaction, and considering the reaction effect and the cost of raw materials, triethylamine is preferred, and the equivalent is preferably 2.0-2.5 equivalents.

[0086] Example 11: Preparation of gleditside

[0087] (4-Aminophenyl)[4-(dimethylamino)-1-piperidinyl]methanone (81.6 g, 0.33 mol) was dissolved in 200 mL of anhydrous THF to obtain solution A, triethylamine (60.7 g, 0.6 mol) was added to solution A, and the temperature was lowered to -10-0 °C. Solution B (22.3 g of triphosgene dissolved in 50 mL of anhydrous THF) was slowly added dropwise to the reaction system, and the temperature was controlled to be <0 °C. After the addition was completed, the mixture was stirred at 0±5 °C for 60 min. A sample was taken and HPLC detection showed that 4% of the starting material remained. 4-(4,6-Dimorpholin-1,3,5-triazin-2-yl)aniline (102.7 g, 0.3 mol) was dissolved in 200 mL of anhydrous THF to obtain solution C, which was added to solution A. 4-Dimethylaminopyridine (DMAP, 1.2 g, 0.01 mol) was added, and the temperature was raised to 20-30 °C. The mixture was stirred for 3 h, a sample was taken and HPLC detection showed that 5% of the starting material remained. The mixture was directly filtered, and the obtained filter cake was first washed with 100 mL of deionized water and then with 200 mL of THF to obtain crude gleditsaid.

[0088] The obtained crude product was added to 150 mL of an ethyl acetate / ethanol mixed solvent (v:v=1:2), heated to 65-75 °C, stirred for 2 h, cooled to 20-30 °C, and continuously stirred for 1 h. The mixture was filtered, the filter cake was first washed with 100 mL of THF and then with 100 mL of ethanol to obtain a white solid wet product. The obtained wet product was dried at 40-50 °C under reduced pressure for 10 h to obtain 144 g of gleditsaid with a purity of 97.5% and a yield of 77.8%.

[0089] Example 12: Preparation of gleditsaid

[0090] (4-Aminophenyl)[4-(dimethylamino)-1-piperidinyl]methanone (81.6 g, 0.33 mol) was dissolved in 200 mL of anhydrous THF to obtain solution A, triethylamine (60.7 g, 0.6 mol) was added to solution A, and the temperature was lowered to -10-0 °C. Solution B (35.6 g of triphosgene dissolved in 50 mL of anhydrous THF) was slowly added dropwise to the reaction system, and the temperature was controlled to be <0 °C. After the addition was completed, the mixture was stirred at 0±5 °C for 60 min, and a sample was taken for HPLC detection. The remaining raw material was 1%. 4-(4,6-Dimorpholin-1,3,5-triazin-2-yl)aniline (102.7 g, 0.3 mol) was dissolved in 200 mL of anhydrous THF to obtain solution C, and solution C was added to solution A. 4-Dimethylaminopyridine (DMAP, 1.2 g, 0.01 mol) was added, the temperature was raised to 20-30 °C, and the mixture was stirred for 3 h. A sample was taken for HPLC detection, and the remaining raw material was 5%. The mixture was directly filtered, and the obtained filter cake was first washed with 100 mL of deionized water and then with 200 mL of THF to obtain crude gleditsaid.

[0091] The obtained crude product was added to 150 mL of a mixed solvent of ethyl acetate / ethanol (v:v = 1:2), heated to 65-75 °C, stirred for 2 h, cooled to 20-30 °C, and continuously stirred for 1 h. The mixture was filtered, the filter cake was first washed with 100 mL of THF and then with 100 mL of ethanol, and a white solid wet product was obtained. The obtained wet product was dried at 40-50 °C under reduced pressure for 10 h to obtain gleditsaid 151.6 g with a purity of 97.9% and a yield of 82.1%.

[0092] Example 13: Preparation of gleditsaid

[0093] (4-Aminophenyl)[4-(dimethylamino)-1-piperidinyl]methanone (81.6 g, 0.33 mol) was dissolved in 200 mL of anhydrous THF to obtain solution A, triethylamine (60.7 g, 0.6 mol) was added to solution A, and the temperature was lowered to -10-0 °C. Solution B (35.6 g of triphosgene dissolved in 50 mL of anhydrous THF) was slowly added dropwise to the reaction system, and the temperature was controlled to be <0 °C. After the addition was completed, the mixture was stirred at 0±5 °C for 60 min, and a sample was taken for HPLC detection. The remaining raw material was 1%. 4-(4,6-Dimorpholin-1,3,5-triazin-2-yl)aniline (102.7 g, 0.3 mol) was dissolved in 200 mL of anhydrous THF to obtain solution C, and solution C was added to solution A. 4-Dimethylaminopyridine (DMAP, 1.2 g, 0.01 mol) was added, the temperature was raised to 20-30 °C, and the mixture was stirred for 3 h. A sample was taken for HPLC detection, and the remaining raw material was 5%. The mixture was directly filtered, and the obtained filter cake was first washed with 100 mL of deionized water and then with 200 mL of THF to obtain crude gleditsaid.

[0094] Example 14: Preparation of gleditsaid

[0095] (4-Aminophenyl)[4-(dimethylamino)-1-piperidinyl]methanone (81.6 g, 0.33 mol) was dissolved in 200 mL of anhydrous THF to obtain solution A, triethylamine (60.7 g, 0.6 mol) was added to solution A, and the temperature was lowered to -10-0 °C, and solution B of triphosgene in THF (29.7 g of triphosgene was dissolved in 50 mL of anhydrous THF to prepare solution B) was slowly added dropwise to the reaction system, and the temperature of the dropwise addition was controlled to be <0 °C, and after the dropwise addition was completed, the mixture was stirred at 0±5 °C for 60 min, and sampling was performed for HPLC detection until the residual raw material was <1%. 4-(4,6-Dimorpholin-1,3,5-triazin-2-yl)aniline (102.7 g, 0.3 mol) was dissolved in 200 mL of anhydrous THF to prepare solution C, and solution C was added to solution A, 4-dimethylaminopyridine (DMAP, 0.6 g, 0.005 mol) was added, the temperature was raised to 20-30 °C, and the mixture was stirred for 3 hours, sampling was performed for HPLC detection until the residual raw material was <2%, and the mixture was directly filtered, and the obtained filter cake was first washed with 100 mL of deionized water, and then washed with 200 mL of THF to obtain crude gleditsaid.

[0096] The obtained crude product was added to 150 mL of a mixed solvent of ethyl acetate / ethanol (v:v=1:2), heated to 65-75 °C, and stirred for 2 hours, the temperature was lowered to 20-30 °C, and the stirring was continued for 1 hour, and then filtered, and the filter cake was first washed with 100 mL of THF, and then washed with 100 mL of ethanol to obtain a white solid wet product, and the obtained wet product was dried at 40-50 °C under reduced pressure for 10 hours to obtain gleditsaid 157.9 g, with a purity of 98.5% and a yield of 85.5%.

[0097] Example 15: Preparation of gleditsaid

[0098] Dissolve (4-aminophenyl)[4-(dimethylamino)-1-piperidinyl]methanone (81.6 g, 0.33 mol) in 200 mL of anhydrous THF to obtain solution A. Add triethylamine (60.7 g, 0.6 mol) to solution A, and cool to -10-0 °C. Slowly drop solution B (29.7 g of triphosgene dissolved in 50 mL of anhydrous THF) into the reaction system, and control the dropping temperature to be <0 °C. After the dropping is completed, stir at 0±5 °C for 60 min. Take a sample for HPLC detection until the residual raw material is <1%. Dissolve 4-(4,6-dimorpholin-1,3,5-triazin-2-yl)aniline (102.7 g, 0.3 mol) in 200 mL of anhydrous THF to obtain solution C. Add solution C to solution A, and add 4-dimethylaminopyridine (DMAP, 2.4 g, 0.02 mol). Warm to 20-30 °C, and stir for 3 h. Take a sample for HPLC detection until the residual raw material is <2%. Directly filter, and wash the obtained filter cake with 100 mL of deionized water, and then with 200 mL of THF to obtain the crude gleditsoside.

[0099] Add the obtained crude product to 150 mL of an ethyl acetate / ethanol mixed solvent (v:v=1:2), heat to 65-75 °C, and stir for 2 h. Cool to 20-30 °C, and continue to stir for 1 h. Filter, wash the filter cake with 100 mL of THF, and then with 100 mL of ethanol to obtain a white solid wet product. Dry the obtained wet product at 40-50 °C under reduced pressure for 10 h to obtain gleditsoside 160.1 g, with a purity of 98.6% and a yield of 86.7%.

[0100] Table 3. Effects of triphosgene and DMAP amounts on quality and yield

[0101]

[0102] As can be seen from the above Table and Examples 4, 11, and 12, under the same conditions, the amount of triphosgene has a great effect on the quality and yield, and needs to be strictly controlled to be 0.33 mol. As can be seen from the comparison of Examples 4, 13, 14, and 15, a small amount of DMAP has a significant catalytic effect, and if DMAP is not added, the reaction is difficult to complete. The amount is preferably greater than 0.0175 equivalent, and further increasing the amount has no obvious effect on the reaction.

Claims

1. A preparation method of Zanidip, comprising the following steps: 1) (4-Aminophenyl)[4-(dimethylamino)-1-piperidinyl]methanone (V) is reacted with triphosgene under the action of a reaction solvent and a base to prepare an isocyanate intermediate (VI); 2) Zanidip is prepared by reacting 4-(4,6-dimorpholin-1,3,5-triazin-2-yl)aniline (IV) with the isocyanate intermediate (VI) under the condition of 4-dimethylaminopyridine DMAP.

2. The method of claim 1, wherein: In step 1), the amount of (4-aminophenyl)[4-(dimethylamino)-1-piperidinyl]methanone (V) added is 1.0-1.3 equivalents; and the amount of triphosgene added is 0.25-0.40 equivalents.

3. The method of claim 2, wherein: In step 1), the amount of (4-aminophenyl)[4-(dimethylamino)-1-piperidinyl]methanone (V) added is 1.0-1.3 equivalents; and the amount of triphosgene added is 0.25-0.40 equivalents.

4. The method of claim 1, wherein: In step 1), the amount of (4-aminophenyl)[4-(dimethylamino)-1-piperidinyl]methanone (V) added is 1.0-1.3 equivalents; and the amount of triphosgene added is 0.25-0.40 equivalents.

5. The method of claim 1, wherein: In step 1), the reaction solvent is anhydrous THF or DCM; the base added is one of triethylamine, dimethylisopropylamine, diisopropylamine, pyridine and N,N-diisopropylethylamine; and the temperature for dropping triphosgene solution is -10-0°C.

6. The method of claim 4, wherein: In step 2), the reaction temperature is 20-30°C; and the amount of 4-dimethylaminopyridine DMAP added is 0.0175-0.0666 equivalents.

7. The method of claim 1, wherein: In step 2), the amount of 4-dimethylaminopyridine DMAP added is 0.0333 equivalents.

8. The method of claim 1, wherein: In step 3), the crystallization solvent used is an alcohol solvent and a mixed solvent system of ethyl acetate or heptane; the heating temperature is 65-75°C; and the crystallization temperature is 20-30°C. The preparation method of the 4-(4,6-dimorpholin-1,3,5-triazin-2-yl)aniline (IV) is as follows: In the second step, 2-chloro-4,6-dimorpholin-4-yl-1,3,5-triazine (II) is dissolved in dry tetrahydrofuran and catalysed with a small amount of Fe 3 + under inert gas protection with a pre-prepared Grignard reagent to form 4-(4,6-dimorpholin-1,3,5-triazin-2-yl)aniline (IV) catalysed with a catalyst.

9. The method of claim 8, wherein: The Fe 3+ The catalyst is iron triacetyl acetonate Fe(acac)3; the inert gas is nitrogen or argon. In the first step, 2-chloro-4,6-dimorpholin-4-yl-1,3,5-triazine (II) is prepared by using trichloro-triazine (I) as a starting material and reacting with morpholine under alkaline conditions; 10. The preparation method according to claim 9, specifically comprising the following steps: In the first step, 2-chloro-4,6-dimorpholin-4-yl-1,3,5-triazine (II) is prepared by using trichloro-triazine (I) as a starting material and reacting with morpholine under alkaline conditions; In the second step, 4-(4,6-dimorpholin-1,3,5-triazin-2-yl)aniline (IV) is prepared by using 2-chloro-4,6-dimorpholin-4-yl-1,3,5-triazine (II) as a raw material, and performing kumada coupling with a previously prepared Grignard reagent (III) under the catalysis of trace Fe(acac)3; In the third step, Zanidip is prepared by using the intermediate 4-(4,6-dimorpholin-1,3,5-triazin-2-yl)aniline (IV) under the condition of 4-dimethylaminopyridine DMAP, and reacting with an isocyanate intermediate (VI) prepared by (4-aminophenyl)[4-(dimethylamino)-1-piperidinyl]methanone (V) and triphosgene; The reaction formula is as follows: 。

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