Preparation method of Geliristis

Abstract

The invention belongs to the technical field of organic synthesis and medicine preparation, and particularly relates to a preparation method of Geliristile. The synthetic route of the preparation method is shortened from five-step reaction reported in literatures to three-step reaction, precious metal palladium or a large amount of heavy metal nickel used as a catalyst in the prior art is omitted, large amount of dangerous reagents such as sodium hydrogen are omitted, and the preparation method is convenient to operate, environmentally friendly and suitable for industrial production. The method is safe, high in total yield, low in raw material cost and suitable for large-scale production.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis and medicine preparation, and particularly relates to a preparation method of Gidalise. Background Art

[0002] Gedatolisib is a highly effective dual inhibitor of PI3K / mTOR that selectively targets all type I developed by Pfizer in the United States. The U.S. FDA has granted it a potential "first-in-class" PI3K / mTOR inhibitor breakthrough therapy designation for the treatment of patients with HR-positive / HER2-negative metastatic breast cancer. The disease has progressed after patients have received CDK4 / 6 inhibitors and non-steroidal aromatase inhibitors. The FDA has granted Gedatolisib a fast track designation as a potential treatment option. Its mechanism of action and pharmacokinetic characteristics are highly different. Compared with isoform-specific PI3K inhibitors or mTOR inhibitors, the simultaneous inhibition of all 4 type I PI3K isoforms and mTOR limits the development of potential drug resistance. According to the Yaorongyun database, Gedatolisib's current trial for metastatic breast cancer in the United States has advanced to clinical phase III, and it is a highly potential new anti-cancer drug.

[0003]

[0004] At present, the preparation methods of Gidalise reported in the literature include the following routes:

[0005] Route 1:

[0006]

[0007] The route is to use trichloroazine (I) as the starting material and morpholine to generate 2-chloro-4,6-dimorpholinyl-1,3,5-triazine (II) through SNAr substitution, and the obtained intermediate II is Suzuki coupled with 4-aminophenylboronic acid pinacol ester (III) to synthesize the key intermediate 4-(4,6-dimorpholinoline-1,3,5-triazine-2-yl) aniline (IV). Then, the obtained intermediate IV is reacted with methyl 4-isocyanatobenzoate (V) to synthesize intermediate VI, and finally the target molecule Gidalis is synthesized through ester hydrolysis and acylation.

[0008] Route 2

[0009]

[0010] This route uses cyanoguanidine and p-nitrobenzonitrile as raw materials. First, the cyclization of s-triazine is achieved through KOH base catalysis to obtain the intermediate 6-(4-nitrophenyl)-1,3,5-triazine-2,4-diamine (3). Then, under the catalysis of sodium hydrogen, it is reacted with 2,2'-dichloroethyl ether (4) to achieve the cyclization of the morpholine ring to obtain the intermediate 4,4'-(6-(4-nitrophenyl)-1,3,5-triazine-2,4-diyl) dimorpholine (5). Then, it is reacted with Raney H2O to obtain the intermediate 6-(4-nitrophenyl)-1,3,5-triazine-2,4-diamine (3). Nickel-catalyzed reduction gave 4-(4,6-dimorpholino-1,3,5-triazine-2-yl)aniline (6), which was then acylated with phenyl chloroformate (7) to give the key intermediate phenyl(4-(4,6-dimorpholino-1,3,5-triazine-2-yl)phenyl)carbamate (8), which was then reacted with (4-aminophenyl)[4-(dimethylamino)-1-piperidinyl]methanone (9) under the catalysis of triethylamine to synthesize the target molecule, Gidalicept.

[0011] The starting materials of this route are easily available, 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 highly toxic and irritating 2,2'-dichloroethyl ether (4) is used as the key raw material to construct the ring, and the yield is only moderate. The fifth step condensation reaction uses DMF as a solvent. This solvent is used in the last step of the raw material and is prone to produce genotoxic impurities. The high temperature of the reaction produces by-products. The yield is only 77%, and the product purity is low, which is not conducive to industrialization.

[0012] From the analysis of the above routes, it can be seen that route 1 has obvious problems: First, the side chain 4-aminophenylboronic acid pinacol ester (III) used in the second step Suzuki coupling is not easy to obtain in the market, and the customization cost is high. In addition, the precious metal palladium catalyst used in this step makes the preparation cost of the intermediate 4-(4,6-dimorpholine-1,3,5-triazine-2-yl) aniline IV high. The reaction uses DMF as a solvent and needs to be carried out under reflux conditions for 24 hours. The reaction time is long and the reaction temperature is high, resulting in high energy consumption and low production efficiency. The post-treatment uses column chromatography for purification, which is not conducive to large-scale production. Secondly, the side chain 4-isocyanatobenzoic acid methyl ester (V) in the third step is not easy to obtain in the market, and the customization cost is high. Finally, the yield of the fifth step condensation reaction is only 52%, and the total yield of the entire route is 32%.

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

[0014] The present invention aims to provide a method for preparing Gidalise in view of the defects of the prior art.

[0015] A method for preparing Gidalise comprises the following steps:

[0016] 1) (4-aminophenyl) [4- (dimethylamino) -1-piperidinyl] ketone (V) and triphosgene in the presence of a reaction solvent and a base to prepare an isocyanate intermediate (VI);

[0017] 2) 4-(4,6-dimorpholine-1,3,5-triazine-2-yl)aniline (IV) reacts with isocyanate intermediate (VI) under alkaline conditions,

[0018] Prepare Gidalise.

[0019] Wherein, in step 1, the amount of (4-aminophenyl) [4- (dimethylamino) -1-piperidinyl] ketone (V) added is 1.0 to 1.3 equivalents; the amount of triphosgene added is (0.25 to 0.40 equivalents).

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

[0021] Step 1) Preparation of isocyanate intermediate VI: the reaction solvent is anhydrous THF or DCM; the added base is one of organic bases such as triethylamine, dimethylisopropylamine, diisopropylamine, pyridine, N,N-diisopropylethylamine, etc.; the temperature of the triphosgene solution is -10 to 0°C;

[0022] Step 2) The reaction temperature is 20-30° C.; the amount of 4-dimethylaminopyridine (DMAP) added is 0.0175-0.0666 equivalents.

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

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

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

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

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

[0028]

[0029] The first step is to use trichloroazine (I) as a starting material and morpholine to prepare 2-chloro-4,6-dimorpholin-4-yl-1,3,5-triazine (II) under alkaline conditions according to the method of reference;

[0030] In the second step, 2-chloro-4,6-dimorpholin-4-yl-1,3,5-triazine (II) is used as the raw material, and under the catalysis of a trace amount of Fe(acac)3, it undergoes kumada coupling with the pre-prepared Grignard reagent (III) to generate 4-(4,6-dimorpholin-1,3,5-triazine-2-yl)aniline (IV);

[0031] The third step is to prepare Gidalise from the intermediate 4-(4,6-dimorpholine-1,3,5-triazine-2-yl)aniline (IV) under alkaline conditions with the isocyanate intermediate (VI) prepared in advance from (4-aminophenyl)[4-(dimethylamino)-1-piperidinyl]methanone (V) and triphosgene.

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

[0033] Step 1, adding cyanuric chloride to an acetone solvent to dissolve, adding 2.0-4.0 equivalents of an organic base, adding 2.0-2.1 equivalents of an acetone solution of morpholine at room temperature, stirring at room temperature for at least 2 hours, sampling and HPLC detection and control, until the raw material cyanuric chloride reacts completely, cooling to -5-5°C after the reaction is completed, slowly adding pre-cooled deionized water, controlling the temperature at -5-5°C, continuing to stir for at least 1 hour after the dropwise addition is completed, washing the filter cake obtained after filtering with water, then eluting with acetone, and vacuum drying the obtained solid. The yield of this step is 75-90%, and the purity can reach more than 99.5%.

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

[0035] The first stage, the preparation of Grignard reagent: 4-bromo-N, N-bis(trimethylsilyl)aniline is used as the starting material to prepare the Grignard reagent; the Grignard reagent is prepared by using active metal magnesium powder or magnesium bars to prepare the Grignard reagent, adding Mg (1.02-1.3eq) and I2 (0.005-0.05w), using anhydrous tetrahydrofuran as the solvent, stirring and heating to 50-70°C, continuing to stir for more than 1 hour, and dropping a portion (about 10% w / w) of 4-bromo-N, N-bis(trimethylsilyl)aniline in tetrahydrofuran. The initiation situation is determined by observing the bubbling phenomenon and the color change of the system solution. After successful initiation, the temperature is controlled at 50-70°C, and the remaining tetrahydrofuran solution of 4-bromo-N,N-bis(trimethylsilyl)aniline is added dropwise. The mixture is stirred for at least 1 hour, and samples are taken for testing in the middle until the 4-bromo-N,N-bis(trimethylsilyl)aniline reacts completely. The reaction system is cooled to 0-10°C and set aside. The obtained Grignard reagent solution can be directly used for the next stage of Kumada coupling reaction without further treatment.

[0036] The second stage, Kumada coupling: using anhydrous tetrahydrofuran as solvent, add the product 2-chloro-4,6-dimorpholine-4-yl-1,3,5-triazine of step 1, stir until completely dissolved, add Fe(acac)3 (0.01w~0.05w) at room temperature, add dropwise the Grignard reagent solution prepared in the first stage, control the dropping temperature at 25~35℃, keep warm and stir for at least 2 hours, and detect by central control HPLC. After the reaction is complete, add acetic acid aqueous solution or dilute hydrochloric acid aqueous solution, stir at room temperature for at least 1 hour, stand and separate, wash the organic layer with saturated sodium chloride solution, concentrate the obtained organic layer, add ethanol for solvent replacement, slowly cool to -5~5℃, stir for at least 1 hour, filter, and wash the filter cake with an alcohol solvent such as methanol, ethanol or isopropanol to obtain a wet product, and vacuum dry to obtain a light yellow solid powder with a purity of ≥98.5% and a yield of 86~91%. If the product is dark in color or low in purity, it can be slurried or recrystallized using a mixed solvent of ethanol or isopropanol and heptane.

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

[0038] Furthermore, after the kumada coupling reaction in the second stage is completed, the concentration of the added dilute hydrochloric acid aqueous solution is 5% to 10%.

[0039] Furthermore, when the color of the final product obtained in the second stage is too dark, tetrahydrofuran, ethanol or a mixed solvent of isopropanol and heptane is used for re-slurrying.

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

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

[0042] Step 3, preparation of Gidalise:

[0043] Dissolve (4-aminophenyl) [4- (dimethylamino) -1-piperidinyl] ketone (V) in anhydrous THF, add a base such as TEA or DIPEA, cool to -10 to 0°C, slowly drop triphosgene in THF solution into the above solution, control the dropping temperature to <0°C, stir at 0±5°C for more than 30 minutes after the dropping is completed, take a sample for HPLC detection, until the remaining raw material is less than 1%. After the reaction is completed, add the THF solution of 4- (4,6-dimorpholine-1,3,5-triazine-2-yl) aniline (II) into the above isocyanate (VI) solution, add a catalytic amount of DMAP, warm to room temperature and stir for more than 3 hours, solid product gradually precipitates, take a sample for HPLC detection, until the remaining raw material 4- (4,6-dimorpholine-1,3,5-triazine-2-yl) aniline II is less than 2%, filter, wash the filter cake with deionized water first, and then with THF to obtain the target product crude product.

[0044] The crude product was added to an ethyl acetate / ethanol mixed solvent, heated to 65-75°C, stirred for at least 1 hour, cooled to room temperature, continued to stir for more than 1 hour, filtered, and the filter cake was washed with THF and ethanol in turn to obtain a white solid wet product, which was dried under reduced pressure below 50°C to obtain Gidalise with a purity of more than 98.5% and a yield of more than 85%.

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

[0046] The invention comprises the following steps: firstly, trichloroazine (I) is used as a starting material and morpholine is reacted under alkaline conditions to prepare 2-chloro-4,6-dimorpholin-4-yl-1,3,5-triazine (II); secondly, a strategy of kumada coupling catalyzed by a trace amount of Fe(acac)3 is adopted to dissolve 2-chloro-4,6-dimorpholin-4-yl-1,3,5-triazine (II) in anhydrous tetrahydrofuran, and reacts with a pre-prepared product under the protection of an inert gas such as nitrogen or argon under the catalysis of a trace amount of Fe(acac)3. The prepared Grignard reagent (III) is subjected to kumada coupling to generate 4-(4,6-dimorpholine-1,3,5-triazine-2-yl)aniline (IV); the third step of the present invention is a key asymmetric urea synthesis step, wherein dimorpholine-1,3,5-triazine-2-yl)aniline (IV) (IV) reacts with an isocyanate intermediate VI prepared in advance by (4-aminophenyl) [4-(dimethylamino)-1-piperidinyl] ketone (V) and triphosgene under alkaline conditions to prepare Gidalise. The preparation method shortens the synthesis route from the five-step reaction reported in the literature to the three-step reaction, which not only eliminates the use of precious metal palladium or a large amount of heavy metal nickel as a catalyst used in the prior art, but also eliminates the large-scale use of dangerous reagents such as sodium hydrogen, and is easy to operate, environmentally friendly, safe, with a high total yield, low raw material cost, and suitable for large-scale production.

[0047] The beneficial effects of the present invention are as follows:

[0048] The second coupling step of the present invention adopts a Kumada coupling strategy catalyzed by a trace amount of Fe(acac)3, and prepares the key intermediate 4-(4,6-dimorpholine-1,3,5-triazine-2-yl)aniline IV in high yield. The reaction conditions are mild and the precious metal palladium catalyst used in the Suzuki coupling in the prior art is eliminated. There is no need to develop a palladium removal process in the subsequent steps, which will significantly reduce the raw material cost of the intermediate IV.

[0049] The third key step of the present invention is a method for synthesizing asymmetric urea. The raw material (4-aminophenyl) [4-(dimethylamino)-1-piperidinyl] ketone (V) for preparing the side chain is first reacted with triphosgene under alkaline conditions to generate an isocyanate intermediate (VI) which is directly used in the next step without further separation, and then reacted with the key intermediate 4-(4,6-dimorpholine-1,3,5-triazine-2-yl) aniline (IV) under alkaline conditions to generate the target product, Gidalis. This reaction is a classic method for preparing asymmetric urea, with mild reaction conditions, simple operation, and high yield. Phosgene and diphosgene are also suitable for this method, but considering the safety and convenience of use, the present invention preferably uses solid triphosgene. DETAILED DESCRIPTION

[0050] The following description is only a preferred embodiment of the present invention and does not limit the present invention. For those skilled in the art, various changes and variations may occur. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

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

[0052] 300 g of cyanuric chloride was added to 1500 mL of acetone to dissolve, 462.6 g of N, N-diisopropylethylamine (2.2 equivalents) was added to the acetone solution, and the pre-prepared acetone solution of morpholine (containing 283.5 g of morpholine, 2.0 equivalents) was slowly added to the acetone solution, and stirred at room temperature for at least 2 hours. The sample was taken and controlled by HPLC until the cyanuric chloride reaction was complete, the reaction solution was cooled to -5 to 5°C, and a pre-cooled 10% hydrochloric acid aqueous solution was added, and the dropping temperature was controlled at -5 to 5°C. After the dropwise addition was completed, stirring was continued for 1 hour, and the filter cake obtained after filtration was first washed with water and then rinsed with methanol. The obtained solid was vacuum dried to obtain 417 g of solid with a purity of 99.6% and a yield of 89.7%.

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

[0054] Stage 1: Preparation of Grignard reagent: Add 30 mL of anhydrous tetrahydrofuran to the reaction flask, add 4.6 g of active magnesium powder (1.1 equivalents) to the reaction flask, add 0.5 g of I2, replace with nitrogen, heat to slight reflux, add 4-bromo-N, N-bis(trimethylsilyl)aniline tetrahydrofuran solution (50 mL of solution contains 5.4 g of 4-bromo-N, N-bis(trimethylsilyl)aniline) to the reaction flask, wait until the reaction system gradually changes from light yellow to brown with bubbling, indicating successful initiation, add the pre-prepared 4-bromo-N, N-bis(trimethylsilyl)aniline tetrahydrofuran solution (250 mL contains 50 g 4-Bromo-N,N-bis(trimethylsilyl)aniline) was slowly added dropwise to the reaction system, the temperature of addition was controlled, stirring was continued for at least 1 hour after the addition was completed, sampling was performed to detect the safety of the reaction of 4-bromo-N,N-bis(trimethylsilyl)aniline, the temperature was lowered to -5 to 5°C, and it was directly used for the next stage of Kumada coupling.

[0055] The second stage: Kumada coupling: add 1000mL of anhydrous tetrahydrofuran to the reaction bottle, add 0.5g of Fe(acac)3 at room temperature and dissolve completely, add 50g of 2-chloro-4,6-dimorpholinyl-1,3,5-triazine prepared in the first step to the reaction system, replace with nitrogen, and stir until dissolved. At room temperature, add the Grignard reagent solution prepared in the first stage to the reaction bottle, control the dropping temperature at 20-30℃, stir for 2 hours after the addition is completed, and take samples for testing until the reaction is complete. 50 mL of water was slowly added dropwise to the reaction system to quench the reaction. After the addition was completed, stirring was continued at room temperature for 1 hour, and the mixture was allowed to stand for stratification. The organic layer was then washed with a saturated sodium chloride solution, and allowed to stand for stratification. A 10% aqueous hydrochloric acid solution was added to the organic layer, and the mixture was stirred at room temperature for 1 hour, and allowed to stand for stratification. The organic layer was concentrated until no liquid flowed out, 250 mL of ethanol was added, and the mixture was continued to be concentrated until no liquid flowed out. A mixed solution of 300 mL of ethanol and 100 mL of water was added, the mixture was heated to 70-80° C., stirred for 1 hour, and then slowly cooled to -5-5° C., stirred for 1 hour, and filtered. The obtained filter cake was slurried with a mixed solvent of 150 mL of ethanol / heptane (50 mL of ethanol: 100 mL of heptane), filtered, washed with water and ethanol successively, and dried to obtain 51.5 g of the product with a yield of 86% and a purity of 99.6%.

[0056] Example 3: Preparation of Gidalise

[0057] Dissolve (4-aminophenyl) [4- (dimethylamino) -1-piperidinyl] ketone (74.2g, 0.3mol) in 200mL of anhydrous THF to obtain solution A, add triethylamine (60.7g, 0.6mol) to solution A, cool to -10 ~ 0°C, slowly drop triphosgene in THF solution B (29.7g triphosgene is dissolved in 50mL of anhydrous THF to prepare solution B) into the reaction system, control the dropping temperature to <0°C, stir at 0±5°C for 60min after the addition is completed, take samples for HPLC detection, until the remaining material is <1%. 4-(4,6-dimorpholine-1,3,5-triazine-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, stirred for 3 hours, and a sample was taken for HPLC detection until the remaining raw material was less than 2%, and then filtered directly. The filter cake was first washed with 100 mL of deionized water and then with 200 mL of THF to obtain the crude product of Gidalisel.

[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, and 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 under reduced pressure at 40-50°C for 10 hours to obtain 158.6 g of Gidalise with a purity of 98.5% and a yield of 85.9%.

[0059] Example 4: Preparation of Gidalise

[0060] Dissolve (4-aminophenyl) [4- (dimethylamino) -1-piperidinyl] ketone (81.6g, 0.33mol) in 200mL of anhydrous THF to obtain solution A, add triethylamine (60.7g, 0.6mol) to solution A, cool to -10 ~ 0°C, slowly drop triphosgene in THF solution B (29.7g triphosgene is dissolved in 50mL of anhydrous THF to prepare solution B) into the reaction system, control the dropping temperature to <0°C, stir at 0±5°C for 60min after the dropping is completed, take samples for HPLC detection, until the remaining material is <1%. 4-(4,6-dimorpholine-1,3,5-triazine-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, stirred for 3 hours, and a sample was taken for HPLC detection until the remaining raw material was less than 2%, and then filtered directly. The filter cake was first washed with 100 mL of deionized water and then with 200 mL of THF to obtain the crude product of Gidalisel.

[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, stirred for 1 hour, filtered, and 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 under reduced pressure at 40-50°C for 10 hours to obtain 160.3 g of Gidalise with a purity of 98.8% and a yield of 86.8%.

[0062] Example 5: Preparation of Gidalise

[0063] Dissolve (4-aminophenyl) [4- (dimethylamino) -1-piperidinyl] ketone (89g, 0.36mol) in 200mL of anhydrous THF to obtain solution A, add triethylamine (60.7g, 0.6mol) to solution A, cool to -10 ~ 0°C, slowly drop triphosgene in THF solution B (29.7g triphosgene is dissolved in 50mL of anhydrous THF to prepare solution B) into the reaction system, control the dropping temperature to <0°C, stir at 0±5°C for 60min after the dropping is completed, take samples for HPLC detection, until the remaining material is <1%. 4-(4,6-dimorpholine-1,3,5-triazine-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, stirred for 3 hours, and a sample was taken for HPLC detection until the remaining raw material was less than 2%, and then filtered directly. The filter cake was first washed with 100 mL of deionized water and then with 200 mL of THF to obtain the crude product of Gidalisel.

[0064] 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, stirred for 1 hour, filtered, and 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 under reduced pressure at 40-50°C for 10 hours to obtain 160.9 g of Gidalise with a purity of 98.7% and a yield of 87.1%.

[0065] Example 6: Preparation of Gidalise

[0066] Dissolve (4-aminophenyl) [4- (dimethylamino) -1-piperidinyl] ketone (96.5g, 0.39mol) in 200mL of anhydrous THF to obtain solution A, add triethylamine (60.7g, 0.6mol) to solution A, cool to -10 ~ 0°C, slowly drop triphosgene in THF solution B (29.7g triphosgene is dissolved in 50mL of anhydrous THF to prepare solution B) into the reaction system, control the dropping temperature to <0°C, stir at 0±5°C for 60min after the addition is completed, take samples for HPLC detection, until the remaining material is <1%. 4-(4,6-dimorpholine-1,3,5-triazine-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, stirred for 3 hours, and a sample was taken for HPLC detection until the remaining raw material was less than 2%, and then filtered directly. The filter cake was first washed with 100 mL of deionized water and then with 200 mL of THF to obtain the crude product of Gidalisel.

[0067] 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, stirred for 1 hour, filtered, and 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 under reduced pressure at 40-50°C for 10 hours to obtain 160.5 g of Gidalise with a purity of 98.2% and a yield of 86.9%.

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

[0069]

[0070] It can be seen from Table 1 that the amount of (4-aminophenyl)[4-(dimethylamino)-1-piperidinyl]methanone added has a certain influence on the yield of the product, but it does not need to be greatly excessive. Considering the cost, 1.1 to 1.2 equivalents can be preferably used.

[0071] Example 7: Preparation of Gidalise

[0072] Dissolve (4-aminophenyl) [4- (dimethylamino) -1-piperidinyl] ketone (74.2g, 0.3mol) in 200mL of anhydrous THF to obtain solution A, add N, N-diisopropylethylamine (77.5g, 0.6mol) to solution A, cool to -10 ~ 0 ° C, slowly add triphosgene THF solution B (29.7g triphosgene is dissolved in 50mL of anhydrous THF to prepare solution B) to the reaction system dropwise, control the dropping temperature to <0 ° C, stir at 0±5 ° C for 60min after the addition is completed, take samples for HPLC detection, until the remaining material is <1%. 4-(4,6-dimorpholine-1,3,5-triazine-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, stirred for 3 hours, and a sample was taken for HPLC detection until the remaining raw material was less than 2%, and then filtered directly. The filter cake was first washed with 100 mL of deionized water and then with 200 mL of THF to obtain the crude product of Gidalisel.

[0073] 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, stirred for 1 hour, filtered, and 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 under reduced pressure at 40-50°C for 10 hours to obtain 148.3 g of Gidalise with a purity of 98.1% and a yield of 80.3%.

[0074] Example 8: Preparation of Gidalise

[0075] Dissolve (4-aminophenyl) [4- (dimethylamino) -1-piperidinyl] ketone (74.2g, 0.3mol) in 200mL of anhydrous THF to obtain solution A, add triethylamine (36.4g, 0.36mol) to solution A, cool to -10 ~ 0 ° C, slowly drop triphosgene THF solution B (29.7g triphosgene is dissolved in 50mL of anhydrous THF to prepare solution B) into the reaction system, control the dropping temperature to <0 ° C, stir at 0 ± 5 ° C for 60min after the addition is completed, take a sample for HPLC detection, the reaction is incomplete, continue to extend the time, and the reaction raw material still remains 5%. Continue to dissolve 4-(4,6-dimorpholine-1,3,5-triazine-2-yl)aniline (102.7 g, 0.3 mol) in 200 mL of anhydrous THF to prepare solution C, add solution C to solution A, add 4-dimethylaminopyridine (DMAP, 1.2 g, 0.01 mol), raise the temperature to 20-30 ° C, stir for 3 hours, take a sample for HPLC detection, the raw material remains about 6%, directly filter, the filter cake obtained is first washed with 100 mL of deionized water, and then washed with 200 mL of THF to obtain the crude product of Gidalise.

[0076] 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, and 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 under reduced pressure at 40-50°C for 10 hours to obtain 130.2 g of Gidalise with a purity of 97.8% and a yield of 70.5%.

[0077] Example 9: Preparation of Gidalise

[0078] Dissolve (4-aminophenyl) [4- (dimethylamino) -1-piperidinyl] ketone (74.2g, 0.3mol) in 200mL of anhydrous THF to obtain solution A, add triethylamine (45.5g, 0.45mol) to solution A, cool to -10 ~ 0°C, slowly drop triphosgene in THF solution B (29.7g triphosgene is dissolved in 50mL of anhydrous THF to prepare solution B) into the reaction system, control the dropping temperature to <0°C, stir at 0±5°C for 60min after the dropping is completed, take a sample for HPLC detection, the reaction is incomplete, and the time is further extended to 120min, and 2% of the reaction raw material still remains. Continue to dissolve 4-(4,6-dimorpholine-1,3,5-triazine-2-yl)aniline (102.7 g, 0.3 mol) in 200 mL of anhydrous THF to prepare solution C, add solution C to solution A, add 4-dimethylaminopyridine (DMAP, 1.2 g, 0.01 mol), raise the temperature to 20-30°C, stir for 3 hours, take samples for HPLC detection, until the raw material remains about 3%, directly filter, and wash the filter cake with 100 mL of deionized water and then with 200 mL of THF to obtain the crude product of Gidalise.

[0079] 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, stirred for 1 hour, filtered, and 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 under reduced pressure at 40-50°C for 10 hours to obtain 145.5 g of Gidalise with a purity of 98.1% and a yield of 78.8%.

[0080] Example 10: Preparation of Gidalise

[0081] Dissolve (4-aminophenyl) [4- (dimethylamino) -1-piperidinyl] ketone (74.2g, 0.3mol) in 200mL of anhydrous THF to obtain solution A, add triethylamine (75.9g, 0.75mol) to solution A, cool to -10 ~ 0°C, slowly drop triphosgene in THF solution B (29.7g triphosgene is dissolved in 50mL of anhydrous THF to prepare solution B) into the reaction system, control the dropping temperature to <0°C, stir at 0±5°C for 60min after the dropping is completed, take a sample for HPLC detection, the reaction is incomplete, and the time is further extended to 120min, and 2% of the reaction raw material still remains. Continue to dissolve 4-(4,6-dimorpholine-1,3,5-triazine-2-yl)aniline (102.7 g, 0.3 mol) in 200 mL of anhydrous THF to prepare solution C, add solution C to solution A, add 4-dimethylaminopyridine (DMAP, 1.2 g, 0.01 mol), raise the temperature to 20-30°C, stir for 3 hours, take samples for HPLC detection, until the raw material remains about 3%, directly filter, and wash the filter cake with 100 mL of deionized water and then with 200 mL of THF to obtain the crude product of Gidalise.

[0082] 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, stirred for 1 hour, filtered, and 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 under reduced pressure at 40-50°C for 10 hours to obtain 158.1 g of Gidalise with a purity of 98.7% and a yield of 85.6%.

[0083] Table 2. Experimental results of different alkali dosages

[0084] Example Base type Amount of alkali (equivalent) 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 2.5 85.6 98.7

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

[0086] Example 11: Preparation of Gidalise

[0087] Dissolve (4-aminophenyl) [4- (dimethylamino) -1-piperidinyl] ketone (81.6g, 0.33mol) in 200mL of anhydrous THF to obtain solution A, add triethylamine (60.7g, 0.6mol) to solution A, cool to -10 ~ 0°C, slowly drop triphosgene (0.075mol) in THF solution B (22.3g of triphosgene is dissolved in 50mL of anhydrous THF to prepare solution B) into the reaction system, control the dropping temperature to <0°C, stir at 0±5°C for 60min after the dropping is completed, take a sample for HPLC detection, and the remaining raw material is 4%. 4-(4,6-dimorpholine-1,3,5-triazine-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, stirred for 3 hours, and a sample was taken for HPLC detection. The remaining raw material was 5%, and it was directly filtered. The filter cake was first washed with 100 mL of deionized water and then with 200 mL of THF to obtain the crude product of Gidalise.

[0088] 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, stirred for 1 hour, filtered, and 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 under reduced pressure at 40-50°C for 10 hours to obtain 144 g of Gidalise with a purity of 97.5% and a yield of 77.8%.

[0089] Example 12: Preparation of Gidalise

[0090] Dissolve (4-aminophenyl) [4- (dimethylamino) -1-piperidinyl] ketone (81.6g, 0.33mol) in 200mL of anhydrous THF to obtain solution A, add triethylamine (60.7g, 0.6mol) to solution A, cool to -10 ~ 0°C, slowly drop triphosgene (0.12mol) in THF solution B (35.6g of triphosgene is dissolved in 50mL of anhydrous THF to prepare solution B) into the reaction system, control the dropping temperature to <0°C, stir at 0±5°C for 60min after the dropping is completed, take a sample for HPLC detection, and the remaining raw material is 1%. 4-(4,6-dimorpholine-1,3,5-triazine-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, stirred for 3 hours, and a sample was taken for HPLC detection. The remaining raw material was 5%, and it was directly filtered. The filter cake was first washed with 100 mL of deionized water and then with 200 mL of THF to obtain the crude product of Gidalise.

[0091] 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, stirred for 1 hour, filtered, and 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 under reduced pressure at 40-50°C for 10 hours to obtain 151.6 g of Gidalise with a purity of 97.9% and a yield of 82.1%.

[0092] Example 13: Preparation of Gidalise

[0093] Dissolve (4-aminophenyl) [4- (dimethylamino) -1-piperidinyl] ketone (81.6g, 0.33mol) in 200mL of anhydrous THF to obtain solution A, add triethylamine (60.7g, 0.6mol) to solution A, cool to -10 ~ 0°C, slowly drop triphosgene in THF solution B (29.7g triphosgene is dissolved in 50mL of anhydrous THF to prepare solution B) into the reaction system, control the dropping temperature to <0°C, stir at 0±5°C for 60min after the dropping is completed, take samples for HPLC detection, until the remaining material is <1%. 4-(4,6-dimorpholine-1,3,5-triazine-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, and the temperature was directly raised to 20-30°C. Stirring was performed for 3 hours. Sampling was performed for HPLC detection. A large amount of raw material remained. The time was extended to 6 hours. There was no obvious change, and the reaction was terminated.

[0094] Example 14: Preparation of Gidalise

[0095] Dissolve (4-aminophenyl) [4- (dimethylamino) -1-piperidinyl] ketone (81.6g, 0.33mol) in 200mL of anhydrous THF to obtain solution A, add triethylamine (60.7g, 0.6mol) to solution A, cool to -10 ~ 0°C, slowly drop triphosgene in THF solution B (29.7g triphosgene is dissolved in 50mL of anhydrous THF to prepare solution B) into the reaction system, control the dropping temperature to <0°C, stir at 0±5°C for 60min after the dropping is completed, take samples for HPLC detection, until the remaining material is <1%. 4-(4,6-dimorpholine-1,3,5-triazine-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, 0.6 g, 0.005 mol) was added, the temperature was raised to 20-30°C, stirred for 3 hours, and a sample was taken for HPLC detection until the remaining raw material was less than 2%, and then directly filtered. The filter cake was first washed with 100 mL of deionized water and then with 200 mL of THF to obtain the crude product of Gidalise.

[0096] 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, stirred for 1 hour, filtered, and 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 under reduced pressure at 40-50°C for 10 hours to obtain 157.9 g of Gidalise with a purity of 98.5% and a yield of 85.5%.

[0097] Example 15: Preparation of Gidalise

[0098] Dissolve (4-aminophenyl) [4- (dimethylamino) -1-piperidinyl] ketone (81.6g, 0.33mol) in 200mL of anhydrous THF to obtain solution A, add triethylamine (60.7g, 0.6mol) to solution A, cool to -10 ~ 0°C, slowly drop triphosgene in THF solution B (29.7g triphosgene is dissolved in 50mL of anhydrous THF to prepare solution B) into the reaction system, control the dropping temperature to <0°C, stir at 0±5°C for 60min after the dropping is completed, take samples for HPLC detection, until the remaining material is <1%. 4-(4,6-dimorpholine-1,3,5-triazine-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, 2.4 g, 0.02 mol) was added, the temperature was raised to 20-30°C, stirred for 3 hours, and a sample was taken for HPLC detection until the remaining raw material was less than 2%, and then filtered directly. The filter cake was first washed with 100 mL of deionized water and then with 200 mL of THF to obtain the crude product of Gidalise.

[0099] 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, stirred for 1 hour, filtered, and 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 under reduced pressure at 40-50°C for 10 hours to obtain 160.1 g of Gidalise with a purity of 98.6% and a yield of 86.7%.

[0100] Table 3. Effect of triphosgene and DMAP dosage on quality and yield

[0101]

[0102] From the above table, it can be seen that under the same conditions, the amount of triphosgene has a great influence on the quality and yield, and needs to be strictly controlled at 0.33 mol. From the comparison of Examples 4, 13, 14, and 15, it can be seen that a trace amount of DMAP plays an obvious catalytic role. If DMAP is not added, the reaction is difficult to be completed. The amount is preferably greater than 0.0175 equivalents, and further increase in the amount has no obvious effect on the reaction.

Claims

1. A method for preparing Gidalise, comprising the following steps: 1) (4-aminophenyl) [4- (dimethylamino) -1-piperidinyl] ketone (V) and triphosgene in the presence of a reaction solvent and a base to prepare an isocyanate intermediate (VI); 2) 4-(4,6-dimorpholine-1,3,5-triazine-2-yl)aniline (IV) is reacted with an isocyanate intermediate (VI) under alkaline conditions to prepare Gidalise.

2. The preparation method according to claim 1, characterized in that: Step 1: (4-aminophenyl) [4- (dimethylamino) -1-piperidinyl] ketone (V) is added in an amount of 1.0 to 1.3 equivalents; and triphosgene is added in an amount of 0.25 to 0.40 equivalents.

3. The preparation method according to claim 2, characterized in that: The amount of (4-aminophenyl)[4-(dimethylamino)-1-piperidinyl]methanone (V) added is 1.1 to 1.2 equivalents; the amount of triphosgene added is 0.33 equivalents.

4. The preparation method according to claim 1, characterized in that: Step 1) Preparation of isocyanate intermediate VI: the reaction solvent is anhydrous THF or DCM; the added base is one of the organic bases such as triethylamine, dimethylisopropylamine, diisopropylamine, pyridine, N,N-diisopropylethylamine, etc.; the temperature of the triphosgene solution is -10 to 0°C.

5. The preparation method according to claim 1, characterized in that: Step 2) The reaction temperature is 20-30° C.; the amount of 4-dimethylaminopyridine (DMAP) added is 0.0175-0.0666 equivalents.

6. The preparation method according to claim 4, characterized in that: Step 2) 4-dimethylaminopyridine (DMAP) was added in an amount of 0.0333 equivalents.

7. The preparation method according to claim 1, characterized in that: The method also includes step 3) preparation of Gedatolisib: a mixed solvent system of a crystallization solvent alcohol solvent (methanol, ethanol, isopropanol, tert-butanol, etc.) and ethyl acetate or heptane; a heating temperature of 65 to 75° C. and a crystallization temperature of 20 to 30° C.

8. The preparation method according to claim 1, characterized in that: The preparation method of the 4-(4,6-dimorpholine-1,3,5-triazine-2-yl)aniline (IV) is as follows: In the first step, trichloroazine (I) is used as a starting material and morpholine is reacted under alkaline conditions to prepare 2-chloro-4,6-dimorpholin-4-yl-1,3,5-triazine (II); In the second step, 2-chloro-4,6-dimorpholin-4-yl-1,3,5-triazine (II) was dissolved in anhydrous tetrahydrofuran and reacted with a trace amount of Fe 3 + Under the catalysis of the catalyst and under the protection of inert gas, the kumada coupling with the pre-prepared Grignard reagent is carried out to generate 4-(4,6-dimorpholine-1,3,5-triazine-2-yl)aniline (IV).

9. The preparation method according to claim 8, characterized in that: The Fe 3+ The catalyst is iron triacetylacetonate Fe(acac)3; The inert gas is nitrogen or argon.

10. The preparation method according to claim 1, specifically comprising the following steps: The first step is to use tripolychloroazine (I) as a starting material and morpholine to prepare 2-chloro-4,6-dimorpholin-4-yl-1,3,5-triazine (II) under alkaline conditions; In the second step, 2-chloro-4,6-dimorpholin-4-yl-1,3,5-triazine (II) is used as a raw material, and a pre-prepared Grignard reagent (III) is kumada coupled under the catalysis of a trace amount of Fe(acac)3 to generate 4-(4,6-dimorpholin-1,3,5-triazine-2-yl)aniline (IV); In the third step, the intermediate 4-(4,6-dimorpholine-1,3,5-triazine-2-yl)aniline (IV) is reacted with the isocyanate intermediate (VI) prepared in advance from (4-aminophenyl)[4-(dimethylamino)-1-piperidinyl]methanone (V) and triphosgene under alkaline conditions to obtain Gidalise; The reaction formula is as follows:

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