Chiral purification process of loratinib intermediate

Abstract

The invention relates to the technical field of medicines, in particular to a chiral purification process of a loratinib intermediate, which comprises the following steps: S1, carboxyl esterification: adding 4-fluoro-2-(1-ethoxyl)-N, N-bis (1-methylethyl) benzamide into a catalytic mixed solution, controlling the temperature to 25-40 DEG C, adding benzoic anhydride to react for 5-7 hours, detecting the reaction of raw materials by central control TLC (Thin Layer Chromatography), filtering, washing, and drying to obtain the loratinib intermediate. Cooling, performing suction filtration, leaching and drying to obtain a compound III; s2, enzyme catalysis: adding the obtained compound III into an organic solvent, in a nitrogen atmosphere, controlling the temperature at 35-40 DEG C, adding lipase, stirring and reacting until the system does not release heat any more, continuously stirring for 1-2 hours, cooling to room temperature, adsorbing and filtering the obtained reaction liquid, adjusting the pH value to 8-10, extracting and separating liquid, washing, and performing rotary evaporation to obtain a crude product, and purifying through an enzymatic solution to obtain a compound IV; s3, hydrolysis and purification: adding the compound IV into an alcoholic solution, mixing, dropwise adding alkali liquor, stirring and reacting for 1-2 hours at room temperature, tracking the reaction by TLC, adding a saturated sodium bicarbonate solution, extracting, washing, drying, filtering and carrying out rotary evaporation to obtain the 4-fluoro-2-[(1S)-1-ethoxyl]-N, N-bis (1-methylethyl) benzamide. The chiral purification method of the loratinib intermediate is mild in reaction condition, low in cost, high in catalytic efficiency, good in stereoselectivity, simple and convenient in post-treatment operation, easy to industrially catalyze a chiral compound resolution means and capable of being used for industrial production.

Description

Technical Field

[0001] The present application relates to the field of pharmaceutical technology, and in particular to a chiral purification process for lorlatinib intermediates. Background Art

[0002] Lorlatinib (PF-06463922) is an ALK inhibitor from Pfizer, USA. The drug entered clinical trials in 2014 for the treatment of lung cancer. It is a potent dual ALK / ROS1 inhibitor with Ki values ​​of <0.02nM, <0.07nM, and 0.7nM for ROS1, ALK (WTChemicalbook), and ALK (L1196M), respectively. PF-06463922 can induce apoptosis. Pfizer has applied for patents for lorlatinib, including: WO2013132376, WO2014207606, WO2013132376, WO2017058780, CA2937257, and WO2017175091. These patents provide corresponding protection for the dosage form, composition, synthesis, and use of the drug.

[0003] Patent CN109134410A reports a method for synthesizing 5-fluoro-3-methylisobenzofuran-1(3H)-one, a key intermediate of larotrectinib, which uses phthalimide as a starting material and obtains the intermediate through eight steps of nitration, reduction, cyclization, diazotization, bromination, and esterification. It is often necessary to split the left-handed chiral intermediate, which can be selectively reduced using a noble metal catalyst or ring-opened under alkaline conditions, oxidized by a strong oxidant, and then selectively reduced to obtain (S)-5-fluoro-3-methylisobenzofuran-3-one. Both splitting methods use a large amount of organic solvent, have a long synthetic route, high cost, long time consumption, low yield, and difficult to achieve hidden dangers, which can easily lead to incomplete reduction. The post-treatment is generally column-passing, which is not suitable for process treatment, seriously increasing the production cost and not in line with the production concept of green chemistry. Therefore, it is necessary to develop a method for the separation of chiral compounds with short steps, mild reaction conditions, low cost, high catalytic efficiency, good stereoselectivity, simple post-processing operation, and easy industrial catalysis, which breaks through the energy consumption barriers of traditional process routes and is conducive to large-scale industrial development and application. Summary of the invention

[0004] In order to effectively improve the above problems, the present application provides a chiral purification process for lorlatinib intermediates, which has the advantages of high yield, mild reaction conditions, high selectivity and environmental friendliness, and is suitable for industrial production.

[0005] The chiral purification process of the lorlatinib intermediate provided in this application adopts the following technical scheme: The chiral purification process of lorlatinib intermediates comprises the following steps: S1: Carboxyl esterification: 4-fluoro-2-(1-hydroxyethyl)-N,N-di(1-methylethyl)benzamide was added into a mixture of tert-butyl alcohol and DMAP, the temperature was controlled to 25-40°C, benzoic anhydride was added and reacted for 5-7h, and the reaction of the raw material was completed by TLC detection, the temperature was lowered, the mixture was filtered, washed and dried to obtain compound III; S2: Enzyme catalysis: Add the obtained compound III to an organic solvent, control the temperature at 35-40°C under a nitrogen atmosphere, add lipase, stir the reaction until the system no longer releases heat, continue stirring for 1-2 hours and cool to room temperature, filter the obtained reaction solution by adsorption, adjust the pH value to 8-10, extract, separate, wash, and rotary evaporate to obtain a crude product, which is purified by an enzymatic solution to obtain compound IV; S3: Hydrolysis purification: Compound IV is added to the alcohol solution and mixed, then an alkali solution is added dropwise and stirred at room temperature for 1-2 hours. After the reaction is completed by TLC tracking, a saturated sodium bicarbonate solution is added, and the mixture is extracted, washed, dried, filtered, and rotary evaporated to obtain 4-fluoro-2-[(1S)-1-hydroxyethyl]-N,N-di(1-methylethyl)benzamide. The specific synthetic route is shown below: By adopting the above technical scheme, the present application first reacts the intermediate raw material 4-fluoro-2-(1-hydroxyethyl)-N,N-di(1-methylethyl)benzamide for synthesizing lorlatinib with benzoic anhydride under the catalysis of DMAP, and the hydroxyethyl group in 4-fluoro-2-(1-hydroxyethyl)-N,N-di(1-methylethyl)benzamide is subjected to carboxyl esterification reaction to obtain compound III, and then lipase is used as a catalyst for asymmetric synthesis, giving full play to the high specific catalytic selectivity unique to lipase in biotechnology, and splitting the left-handed chiral intermediate. The intermediate, the crude racemic mixture of 4-fluoro-2-(1-hydroxyethyl)-N,N-di(1-methylethyl)benzamide, the intermediate raw material of lorlatinib, is converted into the required single chiral compound V, which effectively avoids the possibility of producing other compounds at the same time. The chiral purity of compound V is effectively improved by further purification by adding enzymatic solution. At the same time, the yield of compound V is also effectively improved by hydrolysis under alkaline conditions and post-treatment rotary evaporation, so that the yield of compound V is stable, thereby achieving good reproducibility.

[0006] Compared with traditional redox processes using precious metal catalysts or strong oxidants, the reaction conditions are mild, the catalyst sources are wide, the dosage is small and the cost is low, the catalytic efficiency is high, the stereoselectivity is good, and a large amount of by-products are avoided during the redox process. The post-processing operation does not use a chromatographic column, and the commercial application prospects are broad. It breaks through the energy consumption barriers of traditional process routes, prevents and controls the pollution caused by chemical engineering at the source, conforms to the development concept of green chemistry, and further enriches the structure of chiral compounds as drug intermediates, providing a skeleton for the subsequent development of multifunctional synthetic routes and drugs.

[0007] In a specific embodiment, in S1, the molar ratio of 4-fluoro-2-(1-hydroxyethyl)-N,N-di(1-methylethyl)benzamide to benzoic anhydride is 1:(0.8-1.6).

[0008] By adopting the above technical scheme and optimizing the molar ratio of the raw materials for the carboxyl esterification reaction, the carboxyl esterification reaction can be stably carried out, which can not only allow the hydroxyethyl group to react completely, but also prevent the reactant from being excessive on one side, thereby increasing the probability of by-product formation, improving the selectivity of the reaction raw materials in the organic reaction, and improving the yield of compound III, and making compound III have a complete crystal form and less impurities.

[0009] In a specific embodiment, in S1, the catalytic mixture includes tert-butanol and DMAP, and the mass ratio of the tert-butanol to DMAP is (20-30):1.

[0010] By adopting the above technical scheme, by selecting tert-butyl alcohol and DMAP catalytic environment, tert-butyl alcohol is used for compound I which is sensitive to anhydride and has large steric hindrance, so as to prevent side reactions with reaction substrates, and DMAP is combined as an asymmetric acyl transfer catalyst, so that the carbonyl protonation of the anhydride makes it easier to be attacked by the highly sterically hindered, low-reactive alcohol hydroxyl group, so that the nucleophilicity of the anhydride is enhanced, the reaction is accelerated, and the mass ratio of tert-butyl alcohol and DMAP is optimized to make the catalytic efficiency of the carboxyl esterification reaction higher, and it is easier to be attacked by the alcohol hydroxyl group nucleophilically, thereby improving the reaction rate and yield, reducing the reaction time and lowering the temperature. If the content of DMAP is too much, the electron-donating effect is enhanced, and side reactions are likely to occur, which in turn reduces the content of compound III.

[0011] In a specific embodiment, in S2, the lipase is Candida antarctica lipase.

[0012] The mass ratio of the compound III to the lipase is (9-12):1.

[0013] By adopting the above technical scheme, the Antarctic Candida lipase has strong chiral selectivity and stereoselectivity, and can be used as a carboxyl ester-specific hydrolase in compound III, with a relatively ideal reaction conversion rate and yield. The lipase and compound III are reacted in a certain mass ratio, so as to promote the conversion of the racemic compound III into a single chiral compound V. The Antarctic Candida lipase B has high substrate specificity for resolving the intermediate of compound III, and its conversion efficiency is high. The obtained compound V has high purity. The applicant has found that within a specific ratio range, the chiral ee value of the one-time resolution of compound III and lipase is relatively stable, the resolution efficiency is higher, and the yield is higher.

[0014] In a specific embodiment, in S2, the organic solvent is one or more of aromatic hydrocarbons, esters, alcohols, and nitrogen-containing compound solvents.

[0015] Preferably, the organic solvent is toluene.

[0016] By adopting the above technical scheme, the organic solvent has higher reaction activity and high solubility with lipase. The use of anhydrous organic solvent toluene for lipase-catalyzed synthesis can further inhibit the hydrolysis activity of lipase, and it is insoluble in water, so that the solubility of lipase in toluene is higher, the enzyme activity is stronger, and the enzyme is easier to recover and reuse. The toluene solvent system is not easy to give up protons, so it is not easy to catalyze the production of conformational isomers, which can improve the conversion efficiency; and compared with other organic solvents, the toluene solvent system has fewer by-products that need to be purified and separated, a higher degree of purification, and a higher yield.

[0017] In a specific implementation scheme, the specific operation of purifying the enzymatic solution is: adding the crude product obtained in S2 to 2-4 times the mass of tert-amyl alcohol, heating to 50-60°C for reaction for 30-55 minutes, cooling to 0-5°C, filtering, rinsing and drying.

[0018] By adopting the above technical scheme, tert-amyl alcohol is used as the enzymatic solvent reaction medium, so that in the process of lipase-catalyzed chiral conversion, the negative effects of the alcohol hydroxyl group of the transesterification reaction substrate and the reaction by-products on the enzyme activity are reduced, the chiral resolution efficiency is improved, the enzyme-catalyzed reaction is under the optimal conditions, the lipase still maintains a high activity and good stability, the substrate chiral conversion rate is improved, and the chiral purity of the resolution product is further improved.

[0019] In a specific implementation scheme, the specific extraction operation in S3 is: adding ethyl acetate, stirring, standing, collecting the organic phase, adding ethyl acetate to the aqueous phase, stirring, standing, collecting the organic phase, and combining the organic phases.

[0020] By adopting the above technical scheme, after extraction with ethyl acetate, the chiral purification product remaining in the aqueous phase is extracted, and the by-products, impurities, etc. are separated to improve the chiral purity of the product.

[0021] In summary, the present application includes at least one of the following beneficial technical effects: 1. The intermediate raw material 4-fluoro-2-(1-hydroxyethyl)-N,N-di(1-methylethyl)benzamide for the synthesis of lorlatinib was reacted with benzoic anhydride under the catalysis of DMAP to obtain compound III, and then lipase was used as a catalyst for asymmetric synthesis, which gave full play to the high specific catalytic selectivity of lipase in biotechnology, split the left-handed chiral intermediate, and converted it into the required single chiral compound V, effectively avoiding the possibility of producing other compounds at the same time, making the yield of compound V stable, and thus making the reproducibility good. Compared with the traditional redox by precious metal catalysis or strong oxidant, the reaction conditions are mild, the catalyst source is wide, the amount is small, the cost is low, the catalytic efficiency is high, the stereoselectivity is good, and a large number of by-products are avoided during the redox process. The post-treatment operation does not use the method of passing through the chromatographic column, which further enriches the structure of chiral compounds as drug intermediates and provides a skeleton for the subsequent development of multifunctional synthetic routes and drugs.

[0022] 2. Antarctic Candida lipase has strong chiral selectivity and stereoselectivity, and can be used as a carboxyl ester-specific hydrolase in compound III, with ideal reaction conversion rate and yield. The lipase and compound III are reacted in a certain mass ratio to promote the conversion of the racemic compound III into a single chiral compound V. Antarctic Candida lipase B has high substrate specificity for the resolution of the intermediate of compound III, and its conversion efficiency is high. The obtained compound V has high purity. The applicant has found that the chiral ee value of the one-time resolution of compound III and lipase within a specific ratio range is relatively stable, the resolution efficiency is higher, and the yield is higher.

[0023] 3. By optimizing the molar ratio of the raw materials for the carboxyl esterification reaction, the carboxyl esterification reaction can be carried out stably, which can not only allow the hydroxyethyl group to react completely, but also prevent the reactant from being excessive on one side, increase the probability of by-product formation, improve the selectivity of the reaction raw materials in the organic reaction, increase the yield of compound III, and make compound III complete in crystal form and less in impurities. DETAILED DESCRIPTION

[0024] The lipase in the example is Candida antarctica lipase A (purity 6000 LU / g) purchased from Yingxin Laboratory, trypsin (250 u / mg) purchased from Yuanye Biotechnology, and other raw materials can be obtained commercially.

[0025] Preparation Example 1 Synthesis method of 4-fluoro-2-(1-hydroxyethyl)-N,N-di(1-methylethyl)benzamide: Take 9g of p-fluorobenzoyl chloride and add it to a mixed solution of 162g of triethylamine and dichloromethane in a mass ratio of 1:3, add 3.2g of DMAP, then cool the reaction solution to 0°C, add 11g of diisopropylamine with stirring, raise the temperature to room temperature, stir the reaction overnight, and monitor the completion of the reaction by TLC and GC; wash three times with saturated brine, spin dry the organic layer at 45°C, and recrystallize with petroleum ether to obtain the product; Under nitrogen atmosphere, 149gTHF was cooled to -50°C, and then 6gLDA was slowly added dropwise, and the temperature of the reaction liquid was controlled at -70--60°C. The obtained THF solution of LDA was slowly added dropwise to the above product system, and 8% acetaldehyde THF solution was added dropwise. The reaction was carried out at -50°C for 3h, and 1% dilute hydrochloric acid was added to quench the reaction. The liquids were separated, the aqueous layer was extracted with petroleum ether, and the combined organic layers were spin-dried at 35°C to obtain a crude product, which was recrystallized with ethyl acetate and petroleum ether to obtain the product 4-fluoro-2-(1-hydroxyethyl)-N,N-di(1-methylethyl)benzamide.

[0026] Example 1 The chiral purification process of lorlatinib intermediates comprises the following steps: S1: Carboxyl esterification: 53 g of 4-fluoro-2-(1-hydroxyethyl)-N,N-di(1-methylethyl)benzamide prepared in Preparation Example 1 was added into a mixture of 193.4 g of tert-butyl alcohol and DMAP in a mass ratio of 22:1, the temperature was controlled to 25°C, 44.8 g of benzoic anhydride was added and reacted for 5 h, and the reaction of the raw material was completed by TLC detection, the temperature was lowered to 5°C, filtered, washed and dried to obtain compound III; S2: Enzyme catalysis: 37 g of the obtained compound III was added to 185 mL of toluene. Under a nitrogen atmosphere, the temperature was controlled at 35°C, 3.7 g of lipase was added, and the reaction was stirred until the system no longer released heat. The stirring was continued for 1 hour and the reaction mixture was cooled to room temperature. The obtained reaction solution was filtered through diatomaceous earth, and the mother liquor was poured into 50 ml of water to adjust the pH value to 10. The reaction mixture was allowed to stand for separation, and the organic phase was rinsed with water, washed with saturated brine, dried with magnesium sulfate, and rotary evaporated to obtain a crude product. Four times the mass of tert-amyl alcohol of the crude product was added, and the reaction was heated at 60°C for 30 min. The temperature was lowered to 5°C, filtered, rinsed, and dried at 60°C to obtain compound IV. S3: Hydrolysis purification: 18.6 g of compound IV was added to an alcohol solution (29 g of ethanol and 30 ml of water) and mixed, then 22 g of a 20% sodium hydroxide solution was added dropwise, and the reaction was stirred at room temperature for 2 h. After the reaction was completed, 20 ml of a saturated sodium bicarbonate solution was added dropwise to the solution under stirring, 50 ml of ethyl acetate was added, stirred, and allowed to stand, and the organic phase was collected. 500 ml of ethyl acetate was added to the aqueous phase, stirred, allowed to stand, and the organic phase was collected. The organic phases were combined and rinsed with water, washed with saturated brine, dried with magnesium sulfate, filtered, and evaporated to obtain 4-fluoro-2-[(1S)-1-hydroxyethyl]-N,N-di(1-methylethyl)benzamide. The content of the isomers was detected by HPLC, and the substrate conversion rate was 93%, and the chiral purity of the S-type product was 99%.

[0027] Example 2 The chiral purification process of lorlatinib intermediates comprises the following steps: S1: Carboxyl esterification: 53 g of 4-fluoro-2-(1-hydroxyethyl)-N,N-di(1-methylethyl)benzamide prepared in Preparation Example 1 was added into a mixture of 193.4 g of tert-butyl alcohol and DMAP in a mass ratio of 22:1, the temperature was controlled to 35°C, 44.8 g of benzoic anhydride was added and reacted for 5 h, and the reaction of the raw material was completed by TLC detection, the temperature was lowered to 5°C, filtered, washed and dried to obtain compound III; S2: Enzyme catalysis: 37 g of the obtained compound III was added to 185 mL of toluene. Under a nitrogen atmosphere, the temperature was controlled at 40°C, 3.7 g of lipase was added, and the reaction was stirred until the system no longer released heat. The stirring was continued for 2 h and the reaction mixture was cooled to room temperature. The obtained reaction solution was filtered through diatomaceous earth, and the mother liquor was poured into 50 ml of water to adjust the pH value to 8. The reaction mixture was allowed to stand for separation, and the organic phase was rinsed with water, washed with saturated brine, dried with magnesium sulfate, and rotary evaporated to obtain a crude product. Twice the mass of tert-amyl alcohol of the crude product was added, and the reaction was heated at 50°C for 55 min. The temperature was lowered to 5°C, filtered, rinsed, and dried at 60°C to obtain compound IV. S3: Hydrolysis purification: 18.6 g of compound IV was added to an alcohol solution (29 g of ethanol and 30 ml of water) and mixed, then 22 g of a 20% sodium hydroxide solution was added dropwise, and the reaction was stirred at room temperature for 2 h. After the reaction was completed, 20 ml of a saturated sodium bicarbonate solution was added dropwise to the solution under stirring, 50 ml of ethyl acetate was added, stirred, and allowed to stand, and the organic phase was collected. 500 ml of ethyl acetate was added to the aqueous phase, stirred, allowed to stand, and the organic phase was collected. The organic phases were combined and rinsed with water, washed with saturated brine, dried with magnesium sulfate, filtered, and evaporated to obtain 4-fluoro-2-[(1S)-1-hydroxyethyl]-N,N-di(1-methylethyl)benzamide. The content of isomers was detected by HPLC, and the substrate conversion rate was 93.2%, and the chiral purity of the S-type product was 98.8%.

[0028] Example 3 The chiral purification process of lorlatinib intermediates comprises the following steps: S1: Carboxyl esterification: 53 g of 4-fluoro-2-(1-hydroxyethyl)-N,N-di(1-methylethyl)benzamide prepared in Preparation Example 1 was added into a mixture of 193.4 g of tert-butyl alcohol and DMAP in a mass ratio of 22:1, the temperature was controlled to 25°C, 44.8 g of benzoic anhydride was added and reacted for 5 h, and the reaction of the raw material was completed by TLC detection, the temperature was lowered to 5°C, filtered, washed and dried to obtain compound III; S2: Enzyme catalysis: 37 g of the obtained compound III was added to 185 mL DMA, and the temperature was controlled at 35°C under a nitrogen atmosphere. 3.7 g of lipase was added, and the reaction was stirred until the system no longer released heat. The stirring was continued for 1 hour and the reaction mixture was cooled to room temperature. The obtained reaction solution was filtered through diatomaceous earth, and the mother liquor was poured into 50 ml of water to adjust the pH value to 10. The reaction mixture was allowed to stand for separation, and the organic phase was rinsed with water, washed with saturated brine, dried with magnesium sulfate, and rotary evaporated to obtain a crude product. 4 times the mass of tert-amyl alcohol of the crude product was added, and the reaction was heated at 60°C for 30 min. The temperature was lowered to 5°C, filtered, rinsed, and dried at 60°C to obtain compound IV. S3: Hydrolysis purification: 18.6 g of compound IV was added to an alcohol solution (29 g of ethanol and 30 ml of water) and mixed, then 22 g of a 20% sodium hydroxide solution was added dropwise, and the reaction was stirred at room temperature for 2 h. After the reaction was completed, 20 ml of a saturated sodium bicarbonate solution was added dropwise to the solution under stirring, 50 ml of ethyl acetate was added, stirred, and allowed to stand, and the organic phase was collected. 500 ml of ethyl acetate was added to the aqueous phase, stirred, allowed to stand, and the organic phase was collected. The organic phases were combined and rinsed with water, washed with saturated brine, dried with magnesium sulfate, filtered, and rotary evaporated to obtain 4-fluoro-2-[(1S)-1-hydroxyethyl]-N,N-di(1-methylethyl)benzamide. The content of isomers was detected by HPLC, and the substrate conversion rate was 92.8%, and the chiral purity of the S-type product was 98.4%.

[0029] Example 4 The chiral purification process of lorlatinib intermediates comprises the following steps: S1: Carboxyl esterification: 53 g of 4-fluoro-2-(1-hydroxyethyl)-N,N-di(1-methylethyl)benzamide prepared in Preparation Example 1 was added into a mixture of 193.4 g of tert-butyl alcohol and DMAP in a mass ratio of 22:1, the temperature was controlled to 25°C, 27 g of benzoic anhydride was added and reacted for 5 h, the reaction of the raw material was completed by TLC detection, the temperature was lowered to 5°C, suction filtered, eluted and dried to obtain compound III; S2: Enzyme catalysis: 37 g of the obtained compound III was added to 185 mL of toluene. Under a nitrogen atmosphere, the temperature was controlled at 35°C, 3.7 g of lipase was added, and the reaction was stirred until the system no longer released heat. The stirring was continued for 1 hour and the reaction mixture was cooled to room temperature. The obtained reaction solution was filtered through diatomaceous earth, and the mother liquor was poured into 50 ml of water to adjust the pH value to 10. The reaction mixture was allowed to stand for separation, and the organic phase was rinsed with water, washed with saturated brine, dried with magnesium sulfate, and rotary evaporated to obtain a crude product. Four times the mass of tert-amyl alcohol of the crude product was added, and the reaction was heated at 60°C for 30 min. The temperature was lowered to 5°C, filtered, rinsed, and dried at 60°C to obtain compound IV. S3: Hydrolysis purification: 18.6 g of compound IV was added to an alcohol solution (29 g of ethanol and 30 ml of water) and mixed, then 22 g of a 20% sodium hydroxide solution was added dropwise, and the reaction was stirred at room temperature for 2 h. After the reaction was completed, 20 ml of a saturated sodium bicarbonate solution was added dropwise to the solution under stirring, 50 ml of ethyl acetate was added, stirred, and allowed to stand, and the organic phase was collected. 500 ml of ethyl acetate was added to the aqueous phase, stirred, allowed to stand, and the organic phase was collected. The organic phases were combined and rinsed with water, washed with saturated brine, dried with magnesium sulfate, filtered, and evaporated to obtain 4-fluoro-2-[(1S)-1-hydroxyethyl]-N,N-di(1-methylethyl)benzamide. The content of isomers was detected by HPLC, and the substrate conversion rate was 92.7%, and the chiral purity of the S-type product was 98.1%.

[0030] Example 5 The chiral purification process of lorlatinib intermediates comprises the following steps: S1: Carboxyl esterification: 53 g of 4-fluoro-2-(1-hydroxyethyl)-N,N-di(1-methylethyl)benzamide prepared in Preparation Example 1 was added into a mixture of 193.4 g of tert-butyl alcohol and DMAP in a mass ratio of 20:3, the temperature was controlled to 25°C, 44.8 g of benzoic anhydride was added and reacted for 5 h, and the reaction of the raw material was completed by TLC detection, the temperature was lowered to 5°C, filtered, washed and dried to obtain compound III; S2: Enzyme catalysis: 37 g of the obtained compound III was added to 185 mL of toluene. Under a nitrogen atmosphere, the temperature was controlled at 35°C, 3.7 g of lipase was added, and the reaction was stirred until the system no longer released heat. The stirring was continued for 1 hour and the reaction mixture was cooled to room temperature. The obtained reaction solution was filtered through diatomaceous earth, and the mother liquor was poured into 50 ml of water to adjust the pH value to 10. The reaction mixture was allowed to stand for separation, and the organic phase was rinsed with water, washed with saturated brine, dried with magnesium sulfate, and rotary evaporated to obtain a crude product. Four times the mass of tert-amyl alcohol of the crude product was added, and the reaction was heated at 60°C for 30 min. The temperature was lowered to 5°C, filtered, rinsed, and dried at 60°C to obtain compound IV. S3: Hydrolysis purification: 18.6 g of compound IV was added to an alcohol solution (29 g of ethanol and 30 ml of water) and mixed, then 22 g of a 20% sodium hydroxide solution was added dropwise, and the reaction was stirred at room temperature for 2 h. After the reaction was completed, 20 ml of a saturated sodium bicarbonate solution was added dropwise to the solution under stirring, 50 ml of ethyl acetate was added, stirred, and allowed to stand, and the organic phase was collected. 500 ml of ethyl acetate was added to the aqueous phase, stirred, allowed to stand, and the organic phase was collected. The organic phases were combined and rinsed with water, washed with saturated brine, dried with magnesium sulfate, filtered, and evaporated to obtain 4-fluoro-2-[(1S)-1-hydroxyethyl]-N,N-di(1-methylethyl)benzamide. The content of isomers was detected by HPLC, and the substrate conversion rate was 92.1%, and the chiral purity of the S-type product was 98.6%.

[0031] Example 6 The chiral purification process of lorlatinib intermediates comprises the following steps: S1: Carboxyl esterification: 53 g of 4-fluoro-2-(1-hydroxyethyl)-N,N-di(1-methylethyl)benzamide obtained in Preparation Example 1 was added to a mixture of 193.4 g of tert-butyl alcohol and DMAP in a mass ratio of 22.5:0.5, the temperature was controlled to 25°C, 44.8 g of benzoic anhydride was added and reacted for 5 hours, and the reaction of the raw material was completed by TLC detection, the temperature was lowered to 5°C, filtered, washed and dried to obtain compound III; S2: Enzyme catalysis: 37 g of the obtained compound III was added to 185 mL of toluene In a nitrogen atmosphere, the temperature was controlled at 35°C, 3.7 g of lipase was added, and the reaction was stirred until the system no longer released heat. The stirring was continued for 1 hour and the temperature was cooled to room temperature. The obtained reaction solution was filtered through diatomaceous earth, and the mother liquor was poured into 50 ml of water to adjust the pH value to 10. The liquid was allowed to stand for separation, and the organic phase was rinsed with water, washed with saturated brine, dried with magnesium sulfate, and rotary evaporated to obtain a crude product. 4 times the mass of tert-amyl alcohol of the crude product was added, and the reaction was heated at 60°C for 30 minutes. The temperature was lowered to 5°C, filtered, rinsed, and dried at 60°C to obtain compound IV; S3: Hydrolysis purification: 18.6 g of compound IV was added to an alcohol solution (29 g of ethanol and 30 ml of water) and mixed, then 22 g of a 20% sodium hydroxide solution was added dropwise, and the reaction was stirred at room temperature for 2 h. After the reaction was completed, 20 ml of a saturated sodium bicarbonate solution was added dropwise to the solution under stirring, 50 ml of ethyl acetate was added, stirred, and allowed to stand, and the organic phase was collected. 500 ml of ethyl acetate was added to the aqueous phase, stirred, allowed to stand, and the organic phase was collected. The organic phases were combined and rinsed with water, washed with saturated brine, dried with magnesium sulfate, filtered, and evaporated to obtain 4-fluoro-2-[(1S)-1-hydroxyethyl]-N,N-di(1-methylethyl)benzamide. The content of isomers was detected by HPLC, and the substrate conversion rate was 92.2%, and the chiral purity of the S-type product was 98.5%.

[0032] Example 7 The chiral purification process of lorlatinib intermediates comprises the following steps: S1: Carboxyl esterification: 53 g of 4-fluoro-2-(1-hydroxyethyl)-N,N-di(1-methylethyl)benzamide prepared in Preparation Example 1 was added into a mixture of 193.4 g of tert-butyl alcohol and DMAP in a mass ratio of 22:1, the temperature was controlled to 25°C, 44.8 g of benzoic anhydride was added and reacted for 5 h, and the reaction of the raw material was completed by TLC detection, the temperature was lowered to 5°C, filtered, washed and dried to obtain compound III; S2: Enzyme catalysis: 38 g of the obtained compound III was added to 185 mL of toluene. Under a nitrogen atmosphere, the temperature was controlled at 35°C, 2.7 g of lipase was added, and the reaction was stirred until the system no longer released heat. The stirring was continued for 1 hour and the reaction mixture was cooled to room temperature. The obtained reaction solution was filtered through diatomaceous earth, and the mother liquor was poured into 50 ml of water to adjust the pH value to 10. The reaction mixture was allowed to stand for separation, and the organic phase was rinsed with water, washed with saturated brine, dried with magnesium sulfate, and rotary evaporated to obtain a crude product. Four times the mass of tert-amyl alcohol of the crude product was added, and the reaction was heated at 60°C for 30 min. The temperature was lowered to 5°C, filtered, rinsed, and dried at 60°C to obtain compound IV. S3: Hydrolysis purification: 18.6 g of compound IV was added to an alcohol solution (29 g of ethanol and 30 ml of water) and mixed, then 22 g of a 20% sodium hydroxide solution was added dropwise, and the reaction was stirred at room temperature for 2 h. After the reaction was completed, 20 ml of a saturated sodium bicarbonate solution was added dropwise to the solution under stirring, 50 ml of ethyl acetate was added, stirred, and allowed to stand, and the organic phase was collected. 500 ml of ethyl acetate was added to the aqueous phase, stirred, allowed to stand, and the organic phase was collected. The organic phases were combined and rinsed with water, washed with saturated brine, dried with magnesium sulfate, filtered, and evaporated to obtain 4-fluoro-2-[(1S)-1-hydroxyethyl]-N,N-di(1-methylethyl)benzamide. The content of isomers was detected by HPLC, and the substrate conversion rate was 92.5%, and the chiral purity of the S-type product was 98.0%.

[0033] Example 8 The chiral purification process of lorlatinib intermediates comprises the following steps: S1: Carboxyl esterification: 53 g of 4-fluoro-2-(1-hydroxyethyl)-N,N-di(1-methylethyl)benzamide prepared in Preparation Example 1 was added into a mixture of 193.4 g of tert-butyl alcohol and DMAP in a mass ratio of 22:1, the temperature was controlled to 25°C, 44.8 g of benzoic anhydride was added and reacted for 5 h, and the reaction of the raw material was completed by TLC detection, the temperature was lowered to 5°C, filtered, washed and dried to obtain compound III; S2: Enzyme catalysis: 36.2 g of the obtained compound III was added to 185 mL of toluene. Under a nitrogen atmosphere, the temperature was controlled at 35°C, 4.5 g of lipase was added, and the reaction was stirred until the system no longer released heat. The stirring was continued for 1 hour and the reaction mixture was cooled to room temperature. The obtained reaction solution was filtered through diatomaceous earth, and the mother liquor was poured into 50 ml of water to adjust the pH value to 10. The reaction mixture was allowed to stand for separation, and the organic phase was rinsed with water, washed with saturated brine, dried with magnesium sulfate, and rotary evaporated to obtain a crude product. Four times the mass of tert-amyl alcohol of the crude product was added, and the reaction was heated at 60°C for 30 min. The temperature was lowered to 5°C, filtered, rinsed, and dried at 60°C to obtain compound IV. S3: Hydrolysis purification: 18.6 g of compound IV was added to an alcohol solution (29 g of ethanol and 30 ml of water) and mixed, then 22 g of a 20% sodium hydroxide solution was added dropwise, and the reaction was stirred at room temperature for 2 h. After the reaction was completed, 20 ml of a saturated sodium bicarbonate solution was added dropwise to the solution under stirring, 50 ml of ethyl acetate was added, stirred, and allowed to stand, and the organic phase was collected. 500 ml of ethyl acetate was added to the aqueous phase, stirred, allowed to stand, and the organic phase was collected. The organic phases were combined and rinsed with water, washed with saturated brine, dried with magnesium sulfate, filtered, and rotary evaporated to obtain 4-fluoro-2-[(1S)-1-hydroxyethyl]-N,N-di(1-methylethyl)benzamide. The content of isomers was detected by HPLC, and the substrate conversion rate was 92.0%, and the chiral purity of the S-type product was 98.3%.

[0034] Comparative Example 1 The chiral purification process of lorlatinib intermediates comprises the following steps: S1: Carboxyl esterification: 53 g of 4-fluoro-2-(1-hydroxyethyl)-N,N-di(1-methylethyl)benzamide prepared in Preparation Example 1 was added into a mixture of 193.4 g of tert-butyl alcohol and DMAP in a mass ratio of 22:1, the temperature was controlled to 25°C, 44.8 g of benzoic anhydride was added and reacted for 5 h, and the reaction of the raw material was completed by TLC detection, the temperature was lowered to 5°C, filtered, washed and dried to obtain compound III; S2: Enzyme catalysis: 37 g of the obtained compound III was added to 185 mL of toluene. Under a nitrogen atmosphere, the temperature was controlled at 35°C, 3.7 g of trypsin was added, and the reaction was stirred until the system no longer released heat. The stirring was continued for 1 hour and the reaction mixture was cooled to room temperature. The obtained reaction solution was filtered through diatomaceous earth, and the mother liquor was poured into 50 ml of water to adjust the pH value to 10. The reaction mixture was allowed to stand for separation, and the organic phase was rinsed with water, washed with saturated brine, dried with magnesium sulfate, and rotary evaporated to obtain a crude product. Four times the mass of tert-amyl alcohol of the crude product was added, and the reaction was heated at 60°C for 30 min. The temperature was lowered to 5°C, filtered, rinsed, and dried at 60°C to obtain compound IV. S3: Hydrolysis purification: 18.6 g of compound IV was added to an alcohol solution (29 g of ethanol and 30 ml of water) and mixed, then 22 g of a 20% sodium hydroxide solution was added dropwise, and the reaction was stirred at room temperature for 2 h. After the reaction was completed, 20 ml of a saturated sodium bicarbonate solution was added dropwise to the solution under stirring, 50 ml of ethyl acetate was added, stirred, and allowed to stand, and the organic phase was collected. 500 ml of ethyl acetate was added to the aqueous phase, stirred, allowed to stand, and the organic phase was collected. The organic phases were combined and rinsed with water, washed with saturated brine, dried with magnesium sulfate, filtered, and evaporated to obtain 4-fluoro-2-[(1S)-1-hydroxyethyl]-N,N-di(1-methylethyl)benzamide. The content of isomers was detected by HPLC, and the substrate conversion rate was 92.3%, and the chiral purity of the S-type product was 78.9%.

[0035] Comparative Example 2 The chiral purification process of lorlatinib intermediates comprises the following steps: S1: Carboxyl esterification: 53 g of 4-fluoro-2-(1-hydroxyethyl)-N,N-di(1-methylethyl)benzamide prepared in Preparation Example 1 was added into a mixture of 193.4 g of tert-butyl alcohol and DMAP in a mass ratio of 22:1, the temperature was controlled to 25°C, 44.8 g of benzoic anhydride was added and reacted for 5 h, and the reaction of the raw material was completed by TLC detection, the temperature was lowered to 5°C, filtered, washed and dried to obtain compound III; S2: Enzyme catalysis: 37 g of the obtained compound III was added to 185 mL of toluene. Under a nitrogen atmosphere, the temperature was controlled at 35°C, 3.7 g of lipase was added, and the reaction was stirred until the system no longer released heat. The stirring was continued for 1 hour and the temperature was cooled to room temperature. The obtained reaction solution was filtered through diatomaceous earth, and the mother liquor was poured into 50 mL of water to adjust the pH value to 10. The mixture was allowed to stand for separation, and the organic phase was rinsed with water, washed with saturated brine, dried with magnesium sulfate, and rotary evaporated to obtain a crude product, which was compound IV; S3: Hydrolysis purification: 18.6 g of compound IV was added to an alcohol solution (29 g of ethanol and 30 ml of water) and mixed, then 22 g of a 20% sodium hydroxide solution was added dropwise, and the reaction was stirred at room temperature for 2 h. After the reaction was completed, 20 ml of a saturated sodium bicarbonate solution was added dropwise to the solution under stirring, 50 ml of ethyl acetate was added, stirred, and allowed to stand, and the organic phase was collected. 500 ml of ethyl acetate was added to the aqueous phase, stirred, allowed to stand, and the organic phase was collected. The organic phases were combined and rinsed with water, washed with saturated brine, dried with magnesium sulfate, filtered, and evaporated to obtain 4-fluoro-2-[(1S)-1-hydroxyethyl]-N,N-di(1-methylethyl)benzamide. The content of isomers was detected by HPLC, and the substrate conversion rate was 91.8%, and the chiral purity of the S-type product was 97.2%.

[0036] The chiral purification method of the intermediate of Lorlatinib in the embodiment has mild reaction conditions, a wide range of catalyst sources, a small amount of low cost, high catalytic efficiency, good stereoselectivity, and avoids the generation of a large number of by-products during the oxidation-reduction process. The post-treatment operation does not use a purification method with weak industrial properties such as a chromatographic column. The commercial application prospect is broad, breaking through the energy consumption barrier of the traditional process route, and preventing and controlling the pollution caused by chemical engineering from the source, which is in line with the development concept of green chemistry. Compared with Example 1 and Example 4, it can be seen that by optimizing the molar ratio of the raw materials of the carboxyl esterification reaction, the carboxyl esterification reaction can be stably carried out. The amount of benzoic anhydride is too small, so that the hydroxyethyl cannot be completely reacted, there are more by-products, and separation is difficult, and the yield and purity are affected. Compared with Example 1 and Example 5-6, it can be seen that the present application optimizes the mass ratio of tert-butyl alcohol and DMAP to make the catalytic efficiency of the carboxyl esterification reaction higher, and it is easier to be attacked by the nucleophilic attack of the alcohol hydroxyl group, thereby increasing the reaction rate and yield, reducing the reaction time and reducing the temperature. The excessive content of DMAP enhances the electron-donating effect, and is prone to side reactions, which reduces the content of compound III and reduces the yield. Compared with Example 1, Examples 7-8 and Comparative Example 1, it can be seen that the lipase and compound III are reacted in a certain mass ratio, so that the racemic compound III is promoted to be converted into a single chiral compound V, and the Antarctic Candida lipase B has high substrate specificity for resolving the intermediate of compound III, the chiral ee value of the one-time resolution is relatively stable, the resolution efficiency is higher, and the purity of the obtained compound V is high. By comparing Example 1 and Comparative Example 1, it can be seen that tert-amyl alcohol is used as an enzymatic solvent reaction medium, so that the substrate chiral conversion rate is increased during the lipase-catalyzed chiral conversion process, and the chiral purity of the resolution product is further improved.

[0037] The above are all preferred embodiments of the present application, and the protection scope of the present application is not limited thereto. Therefore, any equivalent changes made according to the structure, shape, and principle of the present application should be included in the protection scope of the present application.

Claims

1. A chiral purification process for lorlatinib intermediates, characterized in that: The steps include: S1: Carboxyl esterification: Add 4-fluoro-2-(1-hydroxyethyl)-N,N-di(1-methylethyl)benzamide into the catalytic mixture, control the temperature to 25-40°C, add benzoic anhydride and react for 5-7h. After the reaction of the raw material is completed by TLC detection, cool down and filter, wash and dry to obtain compound III; S2: Enzyme catalysis: Add the obtained compound III to an organic solvent, control the temperature at 35-40°C under a nitrogen atmosphere, add lipase, stir the reaction until the system no longer releases heat, continue stirring for 1-2 hours and cool to room temperature, filter the obtained reaction solution by adsorption, adjust the pH value to 8-10, extract, separate, wash, and rotary evaporate to obtain a crude product, which is purified by an enzymatic solution to obtain compound IV; S3: Hydrolysis purification: Compound IV was added to the alcohol solution and mixed, then alkali solution was added dropwise and stirred at room temperature for 1-2 hours. After the reaction was completed by TLC tracking, saturated sodium bicarbonate solution was added, and the mixture was extracted, washed, dried, filtered and rotary evaporated to obtain 4-fluoro-2-[(1S)-1-hydroxyethyl]-N,N-di(1-methylethyl)benzamide.

2. The chiral purification process of the lorlatinib intermediate according to claim 1, characterized in that: In S1, the molar ratio of 4-fluoro-2-(1-hydroxyethyl)-N,N-di(1-methylethyl)benzamide to benzoic anhydride is 1:(0.8-1.6).

3. The chiral purification process of lorlatinib intermediate according to claim 1, characterized in that: In S1, the catalytic mixture includes tert-butanol and DMAP, and the mass ratio of the tert-butanol to DMAP is (20-30):

1.

4. The chiral purification process of lorlatinib intermediate according to claim 1, characterized in that: In S2, the lipase is Candida antarctica lipase.

5. The chiral purification process of lorlatinib intermediate according to claim 4, characterized in that: In S2, the mass ratio of compound III to lipase is (9-12):

1.

6. The chiral purification process of lorlatinib intermediate according to claim 1, characterized in that: In S2, the organic solvent is one or more of aromatic hydrocarbons, esters, alcohols, and nitrogen-containing compound solvents.

7. The chiral purification process of lorlatinib intermediate amine according to claim 1, characterized in that: The specific operation of purifying the enzymatic solution is as follows: adding the crude product obtained in S2 to 2-4 times the mass of tert-amyl alcohol, heating to 50-60° C. for reaction for 30-55 min, cooling to 0-5° C., filtering, eluting and drying.

8. The chiral purification process of lorlatinib intermediate according to claim 1, characterized in that: The specific extraction operation in S3 is: adding ethyl acetate, stirring, standing, collecting the organic phase, adding ethyl acetate to the aqueous phase, stirring, standing, collecting the organic phase, and combining the organic phases.

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