A method of synthesizing a tegoprazan intermediate

Abstract

The application discloses a method for synthesizing a tirofiban intermediate, and belongs to the technical field of drug synthesis. The method comprises the following steps: reacting chloroacetyl chloride and 1,2-difluorobenzene in dichloromethane as a solvent under the catalysis of aluminum chloride to obtain a TCAB-1 / 2 solution; performing enzyme catalytic reduction on the TCAB-1 / 2 solution to obtain a TCAB-3 mixed solution; dissolving the TCAB-3 mixed solution in toluene after concentration; condensing the TCAB-3 mixed solution in toluene in the presence of sodium tert-butoxide and triethyl phosphonoacetate to obtain a TCAB-4 toluene solution; performing ammination cyclization on the TCAB-4 toluene solution to obtain a TCAB-5 intermediate; mixing the TCAB-5 intermediate with liquid alkali, oxidizing the mixture by sodium hypochlorite, acidifying the mixture, extracting the mixture with isopropyl acetate to obtain an isopropyl acetate solution containing a TCAB-7 intermediate, and performing salt formation and crystallization on the isopropyl acetate solution to obtain the TCAB-7 intermediate. The method realizes the industrialized production of the tirofiban intermediate, is green and environment-friendly, has a simple route and controllable quality.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis technology, specifically relating to a method for synthesizing ticagloree intermediates. Background Technology

[0002] Ticagrelor is a novel oral antiplatelet drug. Chemically, it belongs to the cyclopentyltriazole pyrimidine class of compounds. Its full chemical name is (1S,2S,3R,5S)-3-[7-{[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5-propylthio-3H-[1,2,3]triazol[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol, with the molecular formula C1. 23 H 28 F2N6O4S has a molecular weight of 522.57. Ticagrelor is an active drug that does not require activation by hepatic cytochrome P450 enzymes, resulting in rapid onset of action. Its molecules selectively bind to P2Y on the platelet surface. 12 The receptor binds reversibly, and by blocking the binding of adenosine diphosphate to the receptor, platelet activation and aggregation can be inhibited.

[0003] Chinese invention patent application CN111205232A discloses a method for synthesizing a ticagrelor intermediate. This method uses diethyl 2-bromo-1,3-malonate as a starting material and proceeds through five steps: N-alkylation, cyclization, thioalkylation, deprotection, and dichloroation to obtain the target product. This method effectively controls the formation of byproducts in the cyclization step by using phthalimide as a more stable amino protecting group.

[0004] However, the above-mentioned schemes mainly rely on traditional stoichiometric reactions (such as N-alkylation and thiourea cyclization). These reactions are usually lengthy, have low atom economy, and some reactions require the use of stoichiometric reagents. In industrial production, they are prone to generating a large number of by-products and wastes, resulting in significant environmental pressure. Summary of the Invention

[0005] The purpose of this invention is to provide a method for synthesizing ticagloride intermediates. By introducing enzyme-catalyzed reduction technology and using biocatalysis to replace traditional chemical reducing agents, the method avoids the use of heavy metal catalysts and harsh reaction conditions, and features high selectivity, mild reaction conditions, and environmental friendliness.

[0006] The objective of this invention can be achieved through the following technical solutions: A method for synthesizing ticagloree intermediates includes the following steps: Step 1: Using dichloromethane as a solvent, react chloroacetyl chloride with 1,2-difluorobenzene under the catalysis of aluminum trichloride to obtain TCAB-1 / 2 solution, which is then reduced by enzyme catalysis to obtain TCAB-3 mixture.

[0007] Step 2: After concentrating the TCAB-3 mixture, dissolve it in toluene and condense it with triethyl phosphonoacetate in the presence of sodium tert-butoxide to obtain a toluene solution of TCAB-4. After amination and cyclization, obtain the intermediate TCAB-5.

[0008] Step 3: Mix the TCAB-5 intermediate with liquid alkali, oxidize with sodium hypochlorite, acidify, and then extract with isopropyl acetate to obtain an isopropyl acetate solution containing the TCAB-7 intermediate. After salting out, the TCAB-7 intermediate is obtained.

[0009] Furthermore, the general structural formula of the ticagloree intermediate is shown in Formula 1: Formula 1.

[0010] Furthermore, the specific preparation steps for the TCAB-1 / 2 solution are as follows: Dichloromethane and aluminum trichloride were added to a reaction vessel and stirred at 0-10℃ for 20-30 min. Chloroacetyl chloride was added dropwise, and stirring was continued for 30-40 min. 1,2-Difluorobenzene was added dropwise at 20-30℃, and the mixture was refluxed at 40-45℃. Samples were taken every 1 hour for testing until the intermediate control indicators were qualified. The mixture was then transferred to a quenching vessel containing drinking water and stirred for 30-40 min. Sodium bicarbonate was added, and the mixture was allowed to stand for 30-40 min to separate into layers. The lower aqueous phase was removed, and the organic phase was retained. The organic phase was washed with drinking water 3-5 times. After each washing, the mixture was allowed to stand for stratification, and the aqueous phase was removed. Samples were taken to test the moisture content (IPC-4: moisture ≤ 0.1%). After passing the test, a TCAB-1 / 2 solution was obtained.

[0011] Furthermore, the mass ratio of dichloromethane, aluminum trichloride, chloroacetyl chloride, 1,2-difluorobenzene, drinking water, and sodium bicarbonate is 1030-1050:319-321:273-275:239-241:1430-1450:5.9-6.1.

[0012] Furthermore, the central control indicators are: IPC-1: 1,2-difluorobenzene ≤ 0.5%; IPC-2: TCAB-1 ≤ 0.5%; IPC-3: TCAB-2 ≤ 0.5%.

[0013] Furthermore, the specific preparation steps of the TCAB-3 mixture are as follows: Add TCAB-1 / 2 solution, isopropanol, purified water, and anhydrous sodium carbonate to a reaction vessel and stir for 20-30 minutes. Then add concentrated enzyme and β-nicotinamide adenine dinucleotide disodium phosphate. Stir at 25-30°C under a nitrogen atmosphere for 12-14 hours, taking samples every 2 hours until the intermediate control (IPC-5 and IPC-6: TCAB-3 ≤ 0.5%) is qualified. Then add diatomaceous earth and stir for 30-40 minutes. Filter through a plate and frame filter press to obtain the TCAB-3 mixture.

[0014] Furthermore, the mass ratio of TCAB-1 / 2 solution, isopropanol, purified water, anhydrous sodium carbonate, concentrated enzyme, β-nicotinamide adenine dinucleotide disodium phosphate, and diatomaceous earth is 1450-1500:238-242:17.8-18.2:1.9-2.1:38.8-39.6:0.104-0.106:47-49.

[0015] Furthermore, the specific preparation steps for the TCAB-4 toluene solution are as follows: Add the TCAB-3 mixture to a concentration vessel and concentrate under reduced pressure until no fraction remains. Add toluene to dissolve the residue, transfer to a reaction vessel, add sodium tert-butoxide, stir for 30-40 min, add triethyl phosphonoacetate dropwise at 20-30℃, react at 50-55℃, take samples every 1 hour for testing until the intermediate control indicators are qualified, cool to room temperature, add 32wt% liquid alkali, stir for 30-40 min, allow to stand and separate, remove the lower aqueous phase, wash the organic phase 1-3 times with drinking water, allow to stand and separate to obtain the TCAB-4 toluene solution.

[0016] Furthermore, the mass ratio of TCAB-3 mixture, toluene, sodium tert-butoxide, triethyl phosphonoacetate, and 32 wt% liquid alkali is 1750-1770:950-970:99-101:245-247:309-315.

[0017] Furthermore, the central control indicators are: IPC-7 and IPC-8: TCAB-4 ≤ 0.5%.

[0018] Furthermore, the specific preparation steps of the TCAB-5 intermediate are as follows: The TCAB-4 toluene solution was transferred to a concentration vessel and concentrated to dryness under reduced pressure. Methanol and liquid ammonia were added, and the reaction vessel was sealed. The reaction was carried out at 30-35℃ for 4-5 hours. Then, sodium methoxide methanol solution and methyl formate were added, and the reaction was continued for 2-3 hours. A sample was taken to test the moisture content (IPC-9: moisture ≤ 1.0%). After passing the test, the solution was concentrated to a viscous state under reduced pressure. Then, the recovered isopropanol was added, and the solution was heated to 50-60℃ to dissolve. Crystallization was carried out at 0-5℃, and the solution was stirred for 2-3 hours. The solution was then centrifuged to obtain a wet cake. The wet cake was washed with isopropanol 3-5 times, centrifuged, and vacuum dried to constant weight. A sample was taken for testing (IPC-10: purity ≥ 99%, unknown single maximum impurity ≤ 0.5%). The solution was then pulverized to obtain the TCAB-5 intermediate. The reaction process is shown below: Furthermore, the mass ratio of TCAB-4 toluene solution, methanol, liquid ammonia, sodium methoxide methanol solution, methyl formate, and recovered isopropanol is 535-540:198-202:57-60:162-166:54-56:238-242.

[0019] Furthermore, the specific preparation steps of the isopropyl acetate solution containing the TCAB-7 intermediate are as follows: Add TCAB-5 intermediate and 32wt% liquid alkali to a reaction vessel and stir for 20-30 min. Add 10wt% sodium hypochlorite solution dropwise at 0-10℃, controlling the temperature not to exceed 20℃. After the addition is complete, continue to keep warm for 2-4 h, taking samples every 1 h for testing until the intermediate control index (IPC-1: TCAB-5 ≤ 2%) is qualified. Then, cool down to 0-10℃, add concentrated hydrochloric acid, controlling the temperature not to exceed 30℃, add isopropyl acetate, stir for 30-40 min, let stand for 30-40 min to separate the layers, remove the lower aqueous phase, extract the aqueous phase again with isopropyl acetate, combine the two organic phases, wash the combined organic phase 1-3 times with drinking water, stir for 20-30 min, let stand for 30-40 min to separate the layers, remove the aqueous phase, add anhydrous magnesium sulfate to the organic phase, stir and dry for 30-40 min, let stand, filter under pressure, collect the filtrate, and obtain an isopropyl acetate solution containing TCAB-7 intermediate.

[0020] Furthermore, the mass ratio of TCAB-5 intermediate, liquid alkali, sodium hypochlorite solution, concentrated hydrochloric acid, isopropyl acetate, and anhydrous magnesium sulfate is 111-113:424-428:443-445:279-281:398-402:9-11.

[0021] Furthermore, the specific preparation steps of the TCAB-7 intermediate are as follows: The isopropyl acetate solution containing the TCAB-7 intermediate was transferred to a concentration vessel and concentrated to dryness under reduced pressure. Toluene was added, and the solution was stirred and dissolved at 40-50°C. Then, a 25wt% isopropanol hydrochloride solution was added, and the mixture was stirred for 30-40 minutes, precipitating a solid. Crystallization was carried out at 0-5°C for 2-3 hours, followed by centrifugation to obtain a wet cake. The wet cake was washed 1-3 times with toluene, centrifuged, and vacuum dried. Samples were taken for testing (IPC-2: loss on drying ≤1.0%). After passing the test, the sample was pulverized to obtain the TCAB-7 intermediate. The reaction process is shown below: Furthermore, the mass ratio of the isopropyl acetate solution containing the TCAB-7 intermediate, toluene, and isopropanol hydrochloride solution is 670-680:221-227:77.4-79.4.

[0022] The beneficial effects of this invention are: 1. This invention achieves a green preparation of ticagrelor intermediates with high purity, low impurities, and no heavy metal residues by introducing an enzyme-catalyzed reduction system, adopting a one-step Hoffman degradation route, and combining quality control throughout the entire process. The overall process yield is high and stable, making it suitable for industrial production.

[0023] 2. This invention introduces a bio-enzyme catalytic system composed of food-grade concentrated enzyme and β-nicotinamide adenine dinucleotide disodium phosphate, which completes the carbonyl reduction reaction with high selectivity under mild conditions. This avoids the use of traditional chemical reducing agents (such as sodium borohydride / nickel chloride), eliminating the risk of the introduction and residue of heavy metal nickel. At the same time, the enzyme catalytic reaction is carried out in a mixed solvent of isopropanol and water, with mild reaction conditions and high selectivity, effectively inhibiting the occurrence of side reactions such as over-reduction and dehalogenation, providing clean reaction materials for subsequent steps, and effectively ensuring the high purity of the final product.

[0024] 3. This invention employs a sodium hypochlorite / liquid alkali system for a one-step Hoffmann degradation reaction, directly converting the amide intermediate into the target amino product. This shortens the synthetic route and effectively avoids the yield loss and impurity accumulation problems caused by the traditional multi-step process of "acid hydrolysis-amino protection-catalytic hydrogenation deprotection". Furthermore, the reaction is carried out under low-temperature control, with mild conditions and simple operation, effectively protecting the integrity of the pyrimidine ring structure and ensuring that the total molar yield of the process remains stable at over 68%. At the same time, it ensures the control of the unknown single largest impurity in the final product, demonstrating the step economy and efficiency of the route design.

[0025] 4. This invention establishes a multi-stage central control index system (IPC-1 to IPC-10) to monitor and strictly control key quality attributes such as reaction endpoints, intermediate impurities, solvent residues, and moisture at each step in real time. This cuts off the impurity transmission chain at the source, helps ensure a stable cyclization reaction environment, high chemical purity, few unknown single impurities, and low drying weight loss. This control system effectively guarantees the reproducibility of the process and the stability of product quality. Detailed Implementation

[0026] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments in the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0027] Example 1: A method for synthesizing ticagloree intermediates, comprising the following steps: S1: Add 1030 kg of dichloromethane and 319 kg of aluminum trichloride to a reaction vessel, stir at 0℃ for 20 min, add 273 kg of chloroacetyl chloride dropwise, continue stirring for 30 min, add 239 kg of 1,2-difluorobenzene dropwise at 20℃, reflux at 40℃, take samples for testing every 1 h until the intermediate control indicators (IPC-1: 1,2-difluorobenzene ≤ 0.5%; IPC-2: TCAB-1 ≤ 0.5%; IPC-3: TCAB-2 ≤ 0.5%) are qualified, transfer to a quenching vessel containing 1430 kg of drinking water, stir for 30 min, add 5.9 kg of sodium bicarbonate, let stand for 30 min to separate the layers, remove the lower aqueous phase, retain the organic phase, wash the organic phase 3 times with drinking water, let stand for separation after each washing, remove the aqueous phase, take samples to test the moisture content (IPC-4: moisture ≤ 0.1%), after passing the test, obtain the TCAB-1 / 2 solution.

[0028] S2: Add 1450 kg of TCAB-1 / 2 solution, 238 kg of isopropanol, 17.8 kg of purified water and 1.9 kg of anhydrous sodium carbonate to the reaction vessel and stir for 20 min. Then add 38.8 kg of concentrated enzyme and 104 g of β-nicotinamide adenine dinucleotide disodium phosphate. Stir at 25 °C under a nitrogen atmosphere for 12 h, taking samples every 2 h during the process until the intermediate control (IPC-5 and IPC-6: TCAB-3 ≤ 0.5%) is qualified. Then add 47 kg of diatomaceous earth and stir for 30 min. Filter through a plate and frame filter press to obtain the TCAB-3 mixture.

[0029] S3: Add 1750 kg of TCAB-3 mixture to a concentrator and concentrate under reduced pressure until no fraction remains. Add 950 kg of toluene to dissolve the residue and transfer it to a reaction vessel. Add 99 kg of sodium tert-butoxide and stir for 30 min. Add 245 kg of triethyl phosphonoacetate dropwise at 20 °C and react at 50 °C. Take samples every 1 h until the intermediate control (IPC-7 and IPC-8: TCAB-4 ≤ 0.5%) is qualified. Cool to room temperature and add 309 kg of 32 wt% liquid alkali. Stir for 30 min, allow to stand and separate the layers, remove the lower aqueous phase, wash the organic phase once with drinking water, and allow to stand and separate the layers to obtain the TCAB-4 toluene solution.

[0030] S4: Transfer 535 kg of TCAB-4 toluene solution to a concentrator, concentrate to dryness under reduced pressure, add 198 kg of methanol and 57 kg of liquid ammonia, seal the reactor, and react at 30°C for 4 h. Then add 162 kg of sodium methoxide methanol solution and 54 kg of methyl formate, and continue reacting for 2 h. Take a sample to test the moisture content (IPC-9: moisture ≤ 1.0%). After passing the test, concentrate to a viscous state under reduced pressure, add 238 kg of recovered isopropanol, heat to 50°C to dissolve, crystallize at 0°C, stir for 2 h, centrifuge to obtain a wet cake, wash the wet cake three times with isopropanol, centrifuge, and vacuum dry to constant weight at 50°C. Take a sample to test (IPC-10: purity ≥ 99%, unknown single maximum impurity ≤ 0.5%), pulverize, and obtain TCAB-5 intermediate.

[0031] S5: Add 111 kg of TCAB-5 intermediate and 424 kg of 32 wt% liquid alkali to the reactor and stir for 20 min. Add 443 kg of 10 wt% sodium hypochlorite solution dropwise at 0℃, controlling the temperature to not exceed 20℃. After the addition is complete, continue to keep warm for 2 h. Take samples every 1 h for testing until the intermediate control index (IPC-1: TCAB-5 ≤ 2%) is qualified. Then cool down to 0℃, add 279 kg of concentrated hydrochloric acid, controlling the temperature to not exceed 30℃, add 398 kg of isopropyl acetate, stir for 30 min, let stand for 30 min to separate the layers, remove the lower aqueous phase, extract the aqueous phase again with 209 kg of isopropyl acetate, combine the two organic phases, wash the combined organic phase once with drinking water, stir for 20 min, let stand for 30 min to separate the layers, remove the aqueous phase, add 9 kg of anhydrous magnesium sulfate to the organic phase, stir and dry for 30 min, let stand, filter under pressure, collect the filtrate, and obtain an isopropyl acetate solution containing TCAB-7 intermediate.

[0032] S6: Transfer 670 kg of isopropyl acetate solution containing TCAB-7 intermediate to a concentration vessel, concentrate to dryness under reduced pressure, add 221 kg of toluene, stir to dissolve at 40 °C, then add 77.4 kg of 25 wt% isopropanol hydrochloride solution, stir for 30 min, precipitate solid, crystallize at 0 °C for 2 h, centrifuge to obtain wet cake, wash the wet cake once with toluene, centrifuge, vacuum dry at 50 °C, take a sample for testing (IPC-2: loss on drying ≤1.0%), after passing the test, pulverize to obtain TCAB-7 intermediate.

[0033] Example 2: A method for synthesizing ticagloree intermediates, comprising the following steps: S1: Add 1040 kg of dichloromethane and 320 kg of aluminum trichloride to a reaction vessel, stir at 5 °C for 25 min, add 274 kg of chloroacetyl chloride dropwise, continue stirring for 35 min, add 240 kg of 1,2-difluorobenzene dropwise at 25 °C, reflux at 42.5 °C, take samples for testing every 1 h until the intermediate control indicators (IPC-1: 1,2-difluorobenzene ≤ 0.5%; IPC-2: TCAB-1 ≤ 0.5%; IPC-3: TCAB-2 ≤ 0.5%) are qualified, transfer to a quenching vessel containing 1440 kg of drinking water, stir for 35 min, add 6.0 kg of sodium bicarbonate, let stand for 35 min to separate the layers, remove the lower aqueous phase, retain the organic phase, wash the organic phase with drinking water 4 times, let stand for separation after each washing, remove the aqueous phase, take samples to test the moisture content (IPC-4: moisture ≤ 0.1%), after passing the test, obtain the TCAB-1 / 2 solution.

[0034] S2: Add 1475 kg of TCAB-1 / 2 solution, 240 kg of isopropanol, 18.0 kg of purified water and 2.0 kg of anhydrous sodium carbonate to a reaction vessel and stir for 25 min. Then add 39.2 kg of concentrated enzyme and 105 g of β-nicotinamide adenine dinucleotide disodium phosphate. Stir at 27.5 °C under a nitrogen atmosphere for 13 h, taking samples every 2 h during the process until the intermediate control (IPC-5 and IPC-6: TCAB-3 ≤ 0.5%) is qualified. Then add 48 kg of diatomaceous earth and stir for 35 min. Filter the mixture through a plate and frame filter press to obtain the TCAB-3 mixture.

[0035] S3: Add 1760 kg of TCAB-3 mixture to a concentration vessel and concentrate under reduced pressure until no fraction remains. Add 960 kg of toluene to dissolve the residue and transfer it to a reaction vessel. Add 100 kg of sodium tert-butoxide and stir for 35 min. Add 246 kg of triethyl phosphonoacetate dropwise at 25 °C and react at 52.5 °C. Take samples every 1 h until the intermediate control (IPC-7 and IPC-8: TCAB-4 ≤ 0.5%) is qualified. Cool to room temperature and add 312 kg of 32 wt% liquid alkali. Stir for 35 min and allow to stand for separation. Remove the lower aqueous phase and wash the organic phase twice with drinking water. Allow to stand for separation to obtain TCAB-4 toluene solution.

[0036] S4: Transfer 537.5 kg of TCAB-4 toluene solution to a concentrator, concentrate to dryness under reduced pressure, add 200 kg of methanol and 58.5 kg of liquid ammonia, seal the reactor, and react at 32.5 °C for 4.5 h. Then add 164 kg of sodium methoxide methanol solution and 55 kg of methyl formate, and continue reacting for 2.5 h. Take a sample to test the moisture content (IPC-9: moisture ≤ 1.0%). After passing the test, concentrate to a viscous state under reduced pressure, add 240 kg of recovered isopropanol, heat to 55 °C to dissolve, crystallize at 2.5 °C, stir for 2.5 h, centrifuge to obtain a wet cake, wash the wet cake 4 times with isopropanol, centrifuge, and vacuum dry to constant weight at 55 °C. Take a sample to test (IPC-10: purity ≥ 99%, unknown single maximum impurity ≤ 0.5%), pulverize, and obtain TCAB-5 intermediate.

[0037] S5: Add 112 kg of TCAB-5 intermediate and 426 kg of 32 wt% liquid alkali to the reactor and stir for 25 min. Add 444 kg of 10 wt% sodium hypochlorite solution dropwise at 5℃, controlling the temperature to not exceed 20℃. After the addition is complete, continue to keep warm for 3 h. Take samples every 1 h for testing until the intermediate control index (IPC-1: TCAB-5 ≤ 2%) is qualified. Then cool down to 5℃, add 280 kg of concentrated hydrochloric acid, controlling the temperature to not exceed 30℃, add 400 kg of isopropyl acetate, stir for 35 min, let stand for 35 min to separate the layers, remove the lower aqueous phase, extract the aqueous phase again with 210 kg of isopropyl acetate, combine the two organic phases, wash the combined organic phase twice with drinking water, stir for 25 min, let stand for 35 min to separate the layers, remove the aqueous phase, add 10 kg of anhydrous magnesium sulfate to the organic phase, stir and dry for 35 min, let stand, filter under pressure, collect the filtrate, and obtain an isopropyl acetate solution containing TCAB-7 intermediate.

[0038] S6: Transfer 675 kg of isopropyl acetate solution containing TCAB-7 intermediate to a concentration vessel, concentrate to dryness under reduced pressure, add 224 kg of toluene, stir to dissolve at 45 °C, then add 78.4 kg of 25 wt% isopropanol hydrochloride solution, stir for 35 min, precipitate solid, crystallize at 2.5 °C for 2.5 h, centrifuge to obtain wet cake, wash the wet cake twice with toluene, centrifuge, vacuum dry at 55 °C, take a sample for testing (IPC-2: loss on drying ≤1.0%), after passing the test, pulverize to obtain TCAB-7 intermediate.

[0039] Example 3: A method for synthesizing ticagloree intermediates, comprising the following steps: S1: Add 1050 kg of dichloromethane and 321 kg of aluminum trichloride to a reaction vessel, stir at 10 °C for 30 min, add 275 kg of chloroacetyl chloride dropwise, continue stirring for 40 min, add 241 kg of 1,2-difluorobenzene dropwise at 30 °C, reflux at 45 °C, take samples for testing every 1 h until the intermediate control indicators (IPC-1: 1,2-difluorobenzene ≤ 0.5%; IPC-2: TCAB-1 ≤ 0.5%; IPC-3: TCAB-2 ≤ 0.5%) are qualified, transfer to a quenching vessel containing 1450 kg of drinking water, stir for 40 min, add 6.1 kg of sodium bicarbonate, let stand for 40 min to separate the layers, remove the lower aqueous phase, retain the organic phase, wash the organic phase 5 times with drinking water, let stand for separation after each washing, remove the aqueous phase, take samples to test the moisture content (IPC-4: moisture ≤ 0.1%), after passing the test, obtain the TCAB-1 / 2 solution.

[0040] S2: Add 1500 kg of TCAB-1 / 2 solution, 242 kg of isopropanol, 18.2 kg of purified water and 2.1 kg of anhydrous sodium carbonate to a reaction vessel and stir for 30 min. Then add 39.6 kg of concentrated enzyme and 106 g of β-nicotinamide adenine dinucleotide disodium phosphate. Stir at 30 °C under a nitrogen atmosphere for 14 h, taking samples every 2 h during the process until the intermediate control (IPC-5 and IPC-6: TCAB-3 ≤ 0.5%) is qualified. Then add 49 kg of diatomaceous earth and stir for 40 min. Filter through a plate and frame filter press to obtain the TCAB-3 mixture.

[0041] S3: Add 1770 kg of TCAB-3 mixture to a concentration vessel and concentrate under reduced pressure until no fraction remains. Add 970 kg of toluene to dissolve the residue and transfer it to a reaction vessel. Add 101 kg of sodium tert-butoxide and stir for 40 min. Add 247 kg of triethyl phosphonoacetate dropwise at 30 °C and react at 55 °C. Take samples every 1 h until the intermediate control (IPC-7 and IPC-8: TCAB-4 ≤ 0.5%) is qualified. Cool to room temperature and add 315 kg of 32 wt% liquid alkali. Stir for 40 min, allow to stand and separate the layers, remove the lower aqueous phase, wash the organic phase three times with drinking water, and allow to stand and separate the layers to obtain the TCAB-4 toluene solution.

[0042] S4: Transfer 540 kg of TCAB-4 toluene solution to a concentrator, concentrate to dryness under reduced pressure, add 202 kg of methanol and 60 kg of liquid ammonia, seal the reactor, and react at 35°C for 5 h. Then add 166 kg of sodium methoxide methanol solution and 56 kg of methyl formate, and continue reacting for 3 h. Take a sample to test the moisture content (IPC-9: moisture ≤ 1.0%). After passing the test, concentrate to a viscous state under reduced pressure, add 242 kg of recovered isopropanol, heat to 60°C to dissolve, crystallize at 5°C, stir for 3 h, centrifuge to obtain a wet cake, wash the wet cake 5 times with isopropanol, centrifuge, and vacuum dry to constant weight at 60°C. Take a sample to test (IPC-10: purity ≥ 99%, unknown single maximum impurity ≤ 0.5%), pulverize, and obtain TCAB-5 intermediate.

[0043] S5: Add 113 kg of TCAB-5 intermediate and 428 kg of 32 wt% liquid alkali to the reactor and stir for 30 min. Add 445 kg of 10 wt% sodium hypochlorite solution dropwise at 10℃, controlling the temperature to not exceed 20℃. After the addition is complete, continue to keep warm for 4 h. Take samples every 1 h for testing until the intermediate control index (IPC-1: TCAB-5 ≤ 2%) is qualified. Then cool down to 10℃, add 281 kg of concentrated hydrochloric acid, controlling the temperature to not exceed 30℃, add 402 kg of isopropyl acetate, stir for 40 min, let stand for 40 min to separate the layers, remove the lower aqueous phase, extract the aqueous phase again with 211 kg of isopropyl acetate, combine the two organic phases, wash the combined organic phase 3 times with drinking water, stir for 30 min, let stand for 40 min to separate the layers, remove the aqueous phase, add 11 kg of anhydrous magnesium sulfate to the organic phase, stir and dry for 40 min, let stand, filter under pressure, collect the filtrate, and obtain an isopropyl acetate solution containing TCAB-7 intermediate.

[0044] S6: Transfer 680 kg of isopropyl acetate solution containing TCAB-7 intermediate to a concentration vessel, concentrate to dryness under reduced pressure, add 227 kg of toluene, stir to dissolve at 50 °C, then add 79.4 kg of 25 wt% isopropanol hydrochloride solution, stir for 40 min, precipitate solid, crystallize at 5 °C for 3 h, centrifuge to obtain wet cake, wash the wet cake 3 times with toluene, centrifuge, vacuum dry at 60 °C, take a sample for testing (IPC-2: loss on drying ≤1.0%), after passing the test, pulverize to obtain TCAB-7 intermediate.

[0045] In Examples 1-3, dichloromethane was selected from Shandong Huijun Chemical Co., Ltd., CAS No. 75-09-2; aluminum trichloride was selected from Tianjin Damao Chemical Reagent Partnership (Limited Partnership), CAS No. 7784-13-6; chloroacetyl chloride was selected from Zibo Yujin Trading Co., Ltd., CAS No. 79-04-9; 1,2-difluorobenzene was selected from Rongsheng New Materials, CAS No. 367-11-3; sodium bicarbonate was selected from Chengdu Kelong Chemical Co., Ltd., CAS No. 144-55-8; and isopropanol was selected from Jinan Xinjiuyao Chemical Co., Ltd. The CAS number is 67-63-0; anhydrous sodium carbonate is from Langfang Naco New Material Technology Co., Ltd., CAS number 497-19-8; the concentrated enzyme is food-grade mannanase, from Shandong Fangchang Biotechnology Co., Ltd., CAS number 37288-54-3; β-nicotinamide adenine dinucleotide disodium phosphate is from Hubei Darli Chemical Co., Ltd., CAS number 24292-60-2; diatomaceous earth is from Lingshou County Wanduo Mineral Products Processing Co., Ltd., model CA-612; toluene is from Guangdong Daxiao Chemical Co., Ltd., CA S is 108-88-3; sodium tert-butoxide is from Wuhan Jixin Yibang Biotechnology Co., Ltd., CAS number 865-48-5; triethyl phosphonoacetate is from Jiangsu Runfeng Synthetic Technology Co., Ltd., CAS number 867-13-0; liquid alkali is from Jinan Xinqianchuan Chemical Co., Ltd., CAS number 1310-73-2; methanol is from Shandong Langcheng Chemical Co., Ltd., CAS number 67-56-1; liquid ammonia is from Tangshan Kexin Chemical Co., Ltd.; sodium methoxide methanol solution is from Jiangsu Renhe Environmental Protection Technology Co., Ltd., CAS number 124- 41-4; Methyl formate was selected from Zibo Yujin Trading Co., Ltd., CAS No. 107-31-3; Sodium hypochlorite solution was selected from Jiangsu Bosite Chemical Technology Co., Ltd., CAS No. 7681-52-9; Isopropyl acetate was selected from Maclean's Reagent Network, CAS No. 108-21-4; Anhydrous magnesium sulfate was selected from Tianjin Jinhui Taiya Chemical Reagent Co., Ltd., CAS No. 7487-88-9; Isopropanol hydrochloride solution was selected from Wuhan Chujiang Haoyu Chemical Technology Co., Ltd., CAS No. 7647-01-0; The remaining raw materials were all commercially available products.

[0046] Comparative Example 1: The difference from Example 1 is that in step S2, 38.8 kg of concentrated enzyme and 104 g of β-nicotinamide adenine dinucleotide disodium phosphate were replaced with 20 kg of sodium borohydride and 5 kg of nickel chloride, while the other steps remained unchanged, to prepare the TCAB-7 intermediate.

[0047] Comparative Example 2: The difference from Example 1 is that the 443 kg 10 wt% sodium hypochlorite solution in step S5 was replaced with 500 kg 50 wt% sulfuric acid solution, and hydrolysis was carried out by reflux at 100°C for 12 h. The hydrolysis product was then reacted with benzyl chloroformate for amino protection, and finally deprotected by catalytic hydrogenation to prepare the TCAB-7 intermediate.

[0048] Comparative Example 3: The difference from Example 1 is that after the reaction in step S1 is completed, it is not monitored by the central control (i.e., the IPC-2 and IPC-3 indicators are not controlled), and is directly transferred to the quenching vessel for subsequent operations. The remaining steps are unchanged to prepare TCAB-7 intermediate.

[0049] For the TCAB-7 intermediates obtained in Examples 1-3 and Comparative Examples 1-3, the chemical purity and content of major impurities were determined by high performance liquid chromatography (HPLC) according to the General Rules of the Chinese Pharmacopoeia and relevant enterprise standards. Heavy metal residues were determined by inductively coupled plasma mass spectrometry (ICP-MS), and loss on drying was determined by the General Rules 0831 method of the Chinese Pharmacopoeia. The total molar yield of the process was calculated, and the results are shown in Table 1. Table 1 Performance test results of TCAB-7 intermediates As can be seen from Table 1, the TCAB-7 intermediates prepared in Examples 1-3 show significant advantages in product purity, impurity control, environmental friendliness, and production efficiency compared to the process routes of Comparative Examples 1-3, which employ traditional chemical reduction, multi-step hydrolysis protection, and relaxed process control.

[0050] In Comparative Example 1, the chemical purity and overall yield of the final product decreased significantly, and excessive heavy metal residues were detected. This may be due to the replacement of the highly selective enzyme-catalyzed reduction system in step S2 with a traditional sodium borohydride / nickel chloride chemical reduction system. Chemical reducing agents have poor selectivity and are prone to over-reduction or dehalogenation side reactions while reducing the target carbonyl group, leading to increased impurity formation. Furthermore, the introduction of nickel chloride results in nickel residues in the final product, posing a risk of heavy metal contamination.

[0051] Comparative Example 2 showed the worst chemical purity and overall process yield in the final product, with increased weight loss on drying, approaching the limit. This is likely due to replacing the one-step Hoffmann degradation reaction in step S5 with a traditional multi-step reaction route of "acid hydrolysis-amino protection-catalytic hydrogenation deprotection". Strong acid hydrolysis conditions may disrupt the pyrimidine ring structure, leading to partial degradation and side reactions, introducing a large number of structurally similar impurities. The two additional steps not only prolong the process route but also introduce additional purification losses and reduced yield. The impurities accumulated in the multi-step reactions are difficult to completely remove through final crystallization.

[0052] In Comparative Example 3, the chemical purity of the final product decreased, the maximum unknown single impurity exceeded the limit, and the total molar yield of the process also decreased slightly. This may be because the product proceeded directly to subsequent operations without central control monitoring after the reaction in step S1. When intermediate impurities fail to meet the acceptable standards before proceeding to the next step, these impurities will be transferred and accumulated in subsequent reactions, ultimately leading to the final product's purity and single impurity index failing to meet the requirements.

[0053] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and variations can be made to these embodiments without departing from the principles and spirit of the invention.

Claims

1. A method for synthesizing a ticagloree intermediate, characterized in that, Includes the following steps: Step 1: Using dichloromethane as a solvent, react chloroacetyl chloride with 1,2-difluorobenzene under the catalysis of aluminum trichloride to obtain TCAB-1 / 2 solution, which is then reduced by enzyme catalysis to obtain TCAB-3 mixture. Step 2: After concentrating the TCAB-3 mixture, dissolve it in toluene, and condense it with triethyl phosphonoacetate in the presence of sodium tert-butoxide to obtain a toluene solution of TCAB-4. After amination and cyclization, obtain the intermediate TCAB-5. Step 3: Mix the TCAB-5 intermediate with liquid alkali, oxidize with sodium hypochlorite, acidify, and then extract with isopropyl acetate to obtain an isopropyl acetate solution containing the TCAB-7 intermediate. After salting out and crystallizing, the TCAB-7 intermediate is obtained. The general structural formula of the ticagloree intermediate is shown in Formula 1: Formula 1.

2. The method for synthesizing a ticagloree intermediate according to claim 1, characterized in that, The specific preparation steps of the TCAB-1 / 2 solution are as follows: Dichloromethane and aluminum trichloride were added to a reaction vessel and stirred at 0-10℃ for 20-30 min. Chloroacetyl chloride was added dropwise, and stirring was continued for 30-40 min. 1,2-Difluorobenzene was added dropwise at 20-30℃, and the mixture was refluxed at 40-45℃. Samples were taken every 1 hour for testing until the intermediate control indicators were qualified. The mixture was then transferred to a quenching vessel containing drinking water and stirred for 30-40 min. Sodium bicarbonate was added, and the mixture was allowed to stand for 30-40 min to separate into layers. The lower aqueous phase was removed, and the organic phase was retained. The organic phase was washed with drinking water 3-5 times. After each washing, the mixture was allowed to stand for separation, and the aqueous phase was removed. The moisture content (IPC-4) was measured: moisture ≤ 0.1%. After passing the test, a TCAB-1 / 2 solution was obtained.

3. The method for synthesizing a ticagloree intermediate according to claim 2, characterized in that, The mass ratio of dichloromethane, aluminum trichloride, chloroacetyl chloride, 1,2-difluorobenzene, drinking water, and sodium bicarbonate is 1030-1050:319-321:273-275:239-241:1430-1450:5.9-6.

1. The specified control parameters are: IPC-1: 1,2-difluorobenzene ≤ 0.5%; IPC-2: TCAB-1 ≤ 0.5%; IPC-3: TCAB-2 ≤ 0.5%.

4. The method for synthesizing a ticagloree intermediate according to claim 1, characterized in that, The specific preparation steps for the TCAB-3 mixture are as follows: Add TCAB-1 / 2 solution, isopropanol, purified water and anhydrous sodium carbonate to a reaction vessel and stir for 20-30 min. Then add concentrated enzyme and β-nicotinamide adenine dinucleotide disodium phosphate. Stir at 25-30℃ under nitrogen atmosphere for 12-14 h, taking samples every 2 h during the process until the central control IPC-5 and IPC-6: TCAB-3 ≤ 0.5%. After passing the test, add diatomaceous earth and stir for 30-40 min. Filter through a plate and frame filter press to obtain TCAB-3 mixture. The mass ratio of the TCAB-1 / 2 solution, isopropanol, purified water, anhydrous sodium carbonate, concentrated enzyme, β-nicotinamide adenine dinucleotide disodium phosphate, and diatomaceous earth is 1450-1500:238-242:17.8-18.2:1.9-2.1:38.8-39.6:0.104-0.106:47-49.

5. The method for synthesizing a ticagloree intermediate according to claim 1, characterized in that, The specific preparation steps for the TCAB-4 toluene solution are as follows: Add the TCAB-3 mixture to a concentration vessel and concentrate under reduced pressure until no fraction remains. Add toluene to dissolve the residue, transfer to a reaction vessel, add sodium tert-butoxide, stir for 30-40 min, add triethyl phosphonoacetate dropwise at 20-30℃, react at 50-55℃, take samples every 1 h for testing until the intermediate control index is qualified, cool to room temperature, add 32wt% liquid alkali, stir for 30-40 min, let stand for separation, remove the lower aqueous phase, wash the organic phase with drinking water 1-3 times, let stand for separation, and obtain TCAB-4 toluene solution; The mass ratio of the TCAB-3 mixture, toluene, sodium tert-butoxide, triethyl phosphonoacetate, and 32 wt% liquid alkali is 1750-1770:950-970:99-101:245-247:309-315. The central control indicators are: IPC-7 and IPC-8: TCAB-4 ≤ 0.5%.

6. The method for synthesizing a ticagloree intermediate according to claim 1, characterized in that, The specific preparation steps for the TCAB-5 intermediate are as follows: The TCAB-4 toluene solution was transferred to a concentration vessel and concentrated to dryness under reduced pressure. Methanol and liquid ammonia were added, the reaction vessel was sealed, and the reaction was carried out at 30-35℃ for 4-5 hours. Then, sodium methoxide methanol solution and methyl formate were added, and the reaction was continued for 2-3 hours. The moisture content was tested using IPC-9: moisture ≤ 1.0%. After passing the test, the solution was concentrated to a viscous state under reduced pressure. Then, the recovered isopropanol was added, and the solution was heated to 50-60℃ to dissolve. Crystallization was carried out at 0-5℃, stirred for 2-3 hours, and centrifuged to obtain a wet cake. The wet cake was washed with isopropanol 3-5 times, centrifuged, and vacuum dried to constant weight. The purity was tested using IPC-10: purity ≥ 99%, and the maximum unknown single impurity ≤ 0.5%. The solution was then pulverized to obtain the TCAB-5 intermediate.

7. The method for synthesizing a ticagloree intermediate according to claim 6, characterized in that, The mass ratio of the TCAB-4 toluene solution, methanol, liquid ammonia, sodium methoxide methanol solution, methyl formate, and recovered isopropanol is 535-540:198-202:57-60:162-166:54-56:238-242.

8. The method for synthesizing a ticagloree intermediate according to claim 1, characterized in that, The specific preparation steps of the isopropyl acetate solution containing the TCAB-7 intermediate are as follows: Add TCAB-5 intermediate and 32wt% liquid alkali to a reaction vessel and stir for 20-30 min. Add 10wt% sodium hypochlorite solution dropwise at 0-10℃, controlling the temperature not to exceed 20℃. After the addition is complete, continue to keep warm for 2-4 h. Take samples every 1 h for testing until the intermediate control index IPC-1: TCAB-5 ≤ 2% is obtained. After passing the test, cool down to 0-10℃, add concentrated hydrochloric acid, controlling the temperature not to exceed 30℃, add isopropyl acetate, stir for 30-40 min, let stand for 30-40 min to separate the layers, remove the lower aqueous phase, extract the aqueous phase again with isopropyl acetate, combine the two organic phases, wash the combined organic phase 1-3 times with drinking water, stir for 20-30 min, let stand for 30-40 min to separate the layers, remove the aqueous phase, add anhydrous magnesium sulfate to the organic phase, stir and dry for 30-40 min, let stand, filter under pressure, and collect the filtrate to obtain an isopropyl acetate solution containing TCAB-7 intermediate.

9. The method for synthesizing a ticagloree intermediate according to claim 8, characterized in that, The mass ratio of the TCAB-5 intermediate, liquid alkali, sodium hypochlorite solution, concentrated hydrochloric acid, isopropyl acetate, and anhydrous magnesium sulfate is 111-113:424-428:443-445:279-281:398-402:9-11.

10. The method for synthesizing a ticagloree intermediate according to claim 1, characterized in that, The specific preparation steps for the TCAB-7 intermediate are as follows: The isopropyl acetate solution containing the TCAB-7 intermediate was transferred to a concentration vessel and concentrated to dryness under reduced pressure. Toluene was added and stirred at 40-50℃ to dissolve the solid. Then, 25wt% isopropanol hydrochloride solution was added and stirred for 30-40 min to precipitate the solid. Crystallization was carried out at 0-5℃ for 2-3 h. The solid was then centrifuged to obtain a wet cake. The wet cake was washed with toluene 1-3 times, centrifuged, and vacuum dried. The IPC-2 was tested: the loss on drying was ≤1.0%. After passing the test, the solid was pulverized to obtain the TCAB-7 intermediate. The mass ratio of the isopropyl acetate solution containing the TCAB-7 intermediate, toluene, and isopropanol hydrochloride solution is 670-680:221-227:77.4-79.4.

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