Preparation method for rolapitant derivative and intermediate thereof

Abstract

The present disclosure relates to a preparation method for a rolapitant derivative and an intermediate thereof. Specifically, the present disclosure relates to a preparation method for a compound represented by formula (II) or a salt thereof, comprising a step of preparing the compound represented by formula (II) or the salt thereof by the reaction of a solution containing a compound represented by formula (I) or a salt thereof, a solution containing a catalyst and a compound represented by formula (I') or a salt thereof, and a solution containing a basic reagent in a continuous flow microreactor.

Description

A method for preparing rorapitane derivatives and intermediates Technical Field

[0001] This disclosure pertains to the pharmaceutical field and specifically relates to a method for preparing a lorapittan derivative and its intermediates. Background Technology

[0002] Tachykinin is a peptide ligand of neurokinin receptors. Neurokinin receptors, such as NK1, NK2, and NK3, are involved in various biological processes. They can be found in the nervous and circulatory systems of mammals as well as in peripheral tissues. Therefore, the regulation of these receptors has been studied for potential treatment or prevention of various physiological disorders, symptoms, or diseases in mammals. On the other hand, drug-induced hemolysis is caused by the massive destruction of red blood cells due to immune factors after a drug enters the body, resulting in clinical manifestations such as anemia, jaundice, and hemolysis of urine. Drug-induced hemolytic anemia can be divided into the following three types: (1) drug-induced immunity, leading to antibody-mediated hemolytic reactions; (2) drugs acting on red blood cells with genetic enzyme defects (e.g., G6PD deficiency); and (3) drug-induced hemolytic reactions to abnormal hemoglobins. The key to treating this disease is to stop using the relevant drugs and control the occurrence of hemolysis to prevent complications.

[0003] US7049320 provides an effective, selective NK1 antagonist of the form rorapitant (B) with beneficial therapeutic and pharmacological properties and good metabolic stability, which can be in the form of a free base or a pharmaceutically acceptable salt, and is suitable for parenteral administration.

[0004] WO2003051840A describes the compound of formula (II-1) as an important intermediate in the synthesis of rorapitant. However, existing technologies (WO2003051840A, WO2003042173A and CN106967000) all use traditional batch reactors, which are unstable and carried out under ultra-low temperature conditions, making them unsuitable for large-scale production.

[0005] Continuous flow microreactors (CFR) technology refers to the technology of conducting chemical reactions in a continuous flow mode using microreactors (including micromixers, microheat exchangers, microseparators, microcontrollers, etc.). Microreactors are chemical process intensification devices with sub-millimeter-level flow channel dimensions, possessing advantages such as high mass and heat transfer efficiency, intrinsic safety, good process repeatability, stable product quality, continuous automated operation, and high space-time efficiency. Cheng Dang et al. reviewed the research progress of continuous flow microreactor technology in realizing the "end-to-end" continuous synthesis and preparation of pharmaceutical raw materials or formulations. Taking ibuprofen as an example, they introduced a six-step continuous flow microreactor technology route from acetophenone to ibuprofen tablets, including catalytic hydrogenation, bromination, Grignard reaction, hydrolysis, crystallization, and drying, achieving efficient preparation of ibuprofen tablets. (Research progress on the application of continuous flow microreactor technology in drug synthesis [J]. Chemical Industry and Engineering Progress, 2019, 38(1):556-575.)

[0006] This disclosure provides a novel method for preparing the compound shown in formula (II-1) using a continuous flow microreactor, thereby synthesizing rorapitant. This method avoids harsh reaction conditions, results in a more stable reaction, and offers greater process operability, which is beneficial for industrial production. Summary of the Invention

[0007] This disclosure provides a method for preparing a compound of formula (II) or a salt thereof, comprising the steps of reacting a solution containing a compound of formula (I) or a salt thereof with a solution containing a catalyst and a compound of formula (I') or a salt thereof, and a solution containing an alkaline reagent in a continuous flow microreactor to prepare a compound of formula (II) or a salt thereof.

[0008] Wherein, R1 is selected from an amino protecting group; X is selected from a halogen.

[0009] In some embodiments, the preparation method includes:

[0010] 1) The step of mixing and reacting a solution containing the compound of formula (I) or its salt with a solution containing a base reagent;

[0011] 2) The step of mixing the above reaction solution with a solution containing a catalyst and the compound of formula (I') or its salt.

[0012] In some embodiments, the preparation method further includes the step of reacting the effluent reaction liquid from the continuous flow microreactor in a batch reactor.

[0013] In some embodiments, the amino protecting group described in this disclosure is selected from acetyl, methoxyacetyl, trifluoroacetyl, trichloroacetyl, neopentanoyl, formyl, benzoyl, phthaloyl, 9-fluorenylmethoxycarbonyl, tert-butoxycarbonyl, and benzyloxycarbonyl. In some embodiments, the amino protecting group described in this disclosure is selected from benzyloxycarbonyl.

[0014] In some embodiments, the alkali reagent is selected from organoalkali metal reagents. In some embodiments, the alkali reagent is selected from organolithium reagents, organosophyllium reagents, organopotassium reagents, organorubium reagents, and organocesium reagents.

[0015] In some embodiments, the base reagent is selected from lithium bis(trimethylsilyl)amino (LiHMDS), sodium bis(trimethylsilyl)amino (NaHMDS), potassium bis(trimethylsilyl)amino (KHMDS), lithium diisopropylamino (LDA), lithium 2,2,6,6-tetramethylpiperidine (TMPLi), lithium tert-butoxide (t-BuOLi), sodium tert-butoxide (t-BuONa), and potassium tert-butoxide (t-BuOK).

[0016] In some embodiments, the base reagent is selected from lithium bis(trimethylsilyl)amino (LiHMDS).

[0017] In some embodiments, the catalyst is selected from iodide catalysts, bromide catalysts, and chloride catalysts. In some embodiments, the catalyst is selected from iodide catalysts.

[0018] In some embodiments, the catalyst is selected from tetrabutylammonium iodide (TBAI), lithium iodide (LiI), sodium iodide (NaI), potassium iodide (KI), cuprous iodide (CuI), tetrabutylphosphine iodide, tetrabutylammonium bromide (TBAB), and tetrabutylchloride (TBAC).

[0019] In some implementations, the catalyst is selected from tetrabutylammonium iodide (TBAI).

[0020] In some embodiments, the solvent in the solution containing the compound of formula (I) or a salt thereof is selected from dichloromethane, dichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran, n-hexane, toluene, N-methylpyrrolidone, and 1,4-dioxane. In some embodiments, the solvent in the solution containing the compound of formula (I) or a salt thereof is selected from dichloromethane.

[0021] In some embodiments, the solvent in the solution containing the catalyst and the compound of formula (I') or a salt thereof is selected from dichloromethane, dichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran, n-hexane, toluene, N-methylpyrrolidone, and 1,4-dioxane. In some embodiments, the solvent in the solution containing the catalyst and the compound of formula (I') or a salt thereof is selected from dichloromethane.

[0022] In some embodiments, the solvent in the solution containing the alkaline reagent is selected from tetrahydrofuran, 2-methyltetrahydrofuran, n-hexane, and toluene.

[0023] In some embodiments, the molar ratio of the compound of formula (I) or a salt thereof to the compound of formula (I') or a salt thereof is 1:1 to 1:2. In some embodiments, the molar ratio of the compound of formula (I) or a salt thereof to the compound of formula (I') or a salt thereof is 1:1.2.

[0024] In some embodiments, the molar ratio of the compound of formula (I) or its salt to the base reagent is 1:0.5-1:3. In some embodiments, the molar ratio of the compound of formula (I) or its salt to the base reagent is 1:2.

[0025] In some embodiments, the molar ratio of the compound of formula (I) or its salt to the catalyst is 1:0.1 to 1:2. In some embodiments, the molar ratio of the compound of formula (I) or its salt to the catalyst is 1:0.5.

[0026] In some embodiments, the retention time of the continuous flow reaction in step 1 of the preparation method is 0.1-30 min. In some embodiments, the retention time of the continuous flow reaction in step 1 of the preparation method can be 0.1 min, 0.25 min, 0.5 min, 0.75 min, 1 min, 1.25 min, 1.5 min, 1.75 min, 2 min, 2.25 min, 2.5 min, 2.75 min, 3 min, 3.25 min, 3.5 min, 3.75 min, 4 min, 4.25 min, 4.5 min, 4.75 min, 5 min, 5.5 min, 6 min, 6.5 min, 7 min, 7.5 min, 8 min, 8.5 min, 9 min, 9.5 min, 10 min, 15 min, 20 min, 25 min, 30 min, or any value between two of these. In some embodiments, the retention time of the continuous flow reaction in step 1 of the preparation method can be 0.1-20 min, 0.1-10 min, or 0.1-5 min. In some embodiments, the retention time of the continuous flow reaction in step 1 of the preparation method can be 0.1-5 min. In some embodiments, the retention time of the continuous flow reaction in step 1 of the preparation method is 3.74 or 1.87 min.

[0027] In some embodiments, the retention time of the continuous flow reaction in step 2 of the preparation method is 0.1-30 min. In some embodiments, the retention time of the continuous flow reaction in step 2 of the preparation method can be 0.1 min, 0.5 min, 1 min, 1.5 min, 2 min, 2.5 min, 3 min, 3.5 min, 4 min, 4.5 min, 5 min, 5.5 min, 6 min, 6.5 min, 7 min, 7.5 min, 8 min, 8.5 min, 9 min, 9.5 min, 10 min, 10.5 min, 11 min, 11.5 min, 12 min, 12.5 min, 13 min, 13.5 min, 14 min, 14.5 min, 15 min, 16 min, 17 min, 18 min, 19 min, 20 min, 25 min, 30 min, or any value between two of these. In some embodiments, the retention time of the continuous flow reaction in step 2 of the preparation method can be 0.1-20 min. In some embodiments, the retention time of the continuous flow reaction in step 2 of the preparation method is 5-15 min. In some embodiments, the retention time of the continuous flow reaction in step 2 of the preparation method is 12.5, 6.66, or 13.33 min.

[0028] In some embodiments, the reaction temperature in step 1 of the preparation method is selected from 0℃ to 78℃. In some embodiments, the reaction temperature in step 1 can be 0℃, -5℃, -10℃, -15℃, -20℃, -25℃, -30℃, -35℃, -40℃, -45℃, -50℃, -55℃, -60℃, -65℃, -70℃, -78℃, or any value between two of these. In some embodiments, the reaction temperature in step 1 can be 0℃-60℃, 0℃-50℃, 0℃-40℃, -20℃-60℃, -40℃-60℃, or -30℃-35℃. In some embodiments, the reaction temperature in step 1 can be 0℃-60℃, -20℃-60℃, -20℃-40℃, -20℃-35℃, or -30℃-35℃. In some embodiments, the reaction temperature of step 1 is -20°C to 40°C. In some embodiments, the reaction temperature of step 1 is -20°C to 35°C.

[0029] In some embodiments, the reaction temperature in step 2 of the preparation method is selected from 0℃ to 78℃. In some embodiments, the reaction temperature in step 2 can be 0℃, -5℃, -10℃, -15℃, -20℃, -25℃, -30℃, -35℃, -40℃, -45℃, -50℃, -55℃, -60℃, -65℃, -70℃, -78℃, or any value between two of these. In some embodiments, the reaction temperature in step 2 can be 0℃-60℃, 0℃-50℃, 0℃-40℃, -20℃-60℃, -40℃-60℃, or -30℃-35℃. In some embodiments, the reaction temperature in step 2 can be 0℃-60℃, -20℃-60℃, -20℃-40℃, -20℃-35℃, or -30℃-35℃. In some embodiments, the reaction temperature of step 2 is -20°C to 40°C. In some embodiments, the reaction temperature of step 2 is -20°C to 35°C.

[0030] In some embodiments, the reaction temperature in the batch reactor during the preparation method is selected from 0°C to 78°C. In some embodiments, the reaction temperature in the batch reactor can be 0°C, -5°C, -10°C, -15°C, -20°C, -25°C, -30°C, -35°C, -40°C, -45°C, -50°C, -55°C, -60°C, -65°C, -70°C, -78°C, or any value between two of these. In some embodiments, the reaction temperature in the batch reactor can be 0°C to 60°C, 0°C to 50°C, 0°C to 40°C, -20°C to 60°C, -40°C to 60°C, or -30°C to 35°C. In some embodiments, the reaction temperature in the batch reactor can be 0°C to 60°C, -20°C to 60°C, -20°C to 40°C, or -30°C to 35°C. In some embodiments, the reaction temperature in the batch reactor is -20°C to 40°C. In some embodiments, the reaction temperature in the batch reactor is -30°C to 35°C. In some embodiments, the flow rate of the solution containing the compound of formula (I) or a salt thereof is 0.1-5000 mL / min. Specifically, it can be 0.5mL / min, 0.6mL / min, 0.7mL / min, 0.8mL / min, 0.9mL / min, 1.0mL / min, 1.5mL / min, 2.0mL / min, 2.5mL / min, 3.0mL / min, 3.5mL / min, 4.0mL / min, 4 .5mL / min, 5.0mL / min, 5.5mL / min, 6.0mL / min, 6.5mL / min, 7.0mL / min, 7.5mL / min, 8.0mL / min, 8.5mL / min, 9.0mL / min, 9.5mL / min, 10mL / min, 11mL / min, The flow rate is 12 mL / min, 13 mL / min, 14 mL / min, 15 mL / min, 20 mL / min, 25 mL / min, 30 mL / min, 35 mL / min, 40 mL / min, 45 mL / min, 50 mL / min, 100 mL / min, 150 mL / min, 200 mL / min, 250 mL / min, 300 mL / min, 350 mL / min, 400 mL / min, 450 mL / min, 500 mL / min, 1000 mL / min, 2000 mL / min, 3000 mL / min, 4000 mL / min, 5000 mL / min, or any value between two of these. In some embodiments, the flow rate of the solution containing the compound shown in formula (I) or a salt thereof is 0.1–100 mL / min. In some embodiments, the flow rate of the solution containing the compound shown in formula (I) or a salt thereof is 0.1–20 mL / min.In some embodiments, the flow rate of the solution containing the compound of formula (I) or a salt thereof is 5.0 mL / min.

[0031] In some embodiments, the flow rate of the solution containing the catalyst and the compound shown in formula (I') or its salt is 0.1-5000 mL / min. Specifically, it can be 0.5 mL / min, 0.6 mL / min, 0.7 mL / min, 0.8 mL / min, 0.9 mL / min, 1.0 mL / min, 1.5 mL / min, 2.0 mL / min, 2.5 mL / min, 3.0 mL / min, 3.5 mL / min, 4.0 mL / min, 4.5 mL / min, 5.0 mL / min, 5.5 mL / min, 6.0 mL / min, 6.5 mL / min, 7.0 mL / min, 7.5 mL / min, 8.0 mL / min, 8.5 mL / min, 9.0 mL / min, 9.5 mL / min, 10 mL / min, 11 mL / min, etc. The flow rate is 12 mL / min, 13 mL / min, 14 mL / min, 15 mL / min, 20 mL / min, 25 mL / min, 30 mL / min, 35 mL / min, 40 mL / min, 45 mL / min, 50 mL / min, 100 mL / min, 150 mL / min, 200 mL / min, 250 mL / min, 300 mL / min, 350 mL / min, 400 mL / min, 450 mL / min, 500 mL / min, 1000 mL / min, 2000 mL / min, 3000 mL / min, 4000 mL / min, 5000 mL / min, or any value between two of these. In some embodiments, the flow rate of the solution containing the catalyst and the compound shown in formula (I') or a salt thereof is 0.1-100 mL / min. In some embodiments, the flow rate of the solution containing the catalyst and the compound shown in formula (I') or a salt thereof is 0.1-20 mL / min. In some embodiments, the flow rate of the solution containing the catalyst and the compound of formula (I') or its salt is 5.0 mL / min.

[0032] In some implementations, the flow rate of the solution containing the alkaline reagent is 0.1-5000 mL / min. Specifically, it can be 0.5 mL / min, 0.6 mL / min, 0.7 mL / min, 0.8 mL / min, 0.9 mL / min, 1.0 mL / min, 1.5 mL / min, 2.0 mL / min, 2.5 mL / min, 3.0 mL / min, 3.5 mL / min, 4.0 mL / min, 4.5 mL / min, 5.0 mL / min, 5.5 mL / min, 6.0 mL / min, 6.5 mL / min, 7.0 mL / min, 7.5 mL / min, 8.0 mL / min, 8.5 mL / min, 9.0 mL / min, 9.5 mL / min, 10 mL / min, 11 mL / min, etc. The flow rate can be 12 mL / min, 13 mL / min, 14 mL / min, 15 mL / min, 20 mL / min, 25 mL / min, 30 mL / min, 35 mL / min, 40 mL / min, 45 mL / min, 50 mL / min, 100 mL / min, 150 mL / min, 200 mL / min, 250 mL / min, 300 mL / min, 350 mL / min, 400 mL / min, 450 mL / min, 500 mL / min, 1000 mL / min, 2000 mL / min, 3000 mL / min, 4000 mL / min, 5000 mL / min, or any value between two of these. In some embodiments, the flow rate of the solution containing the alkaline reagent is 0.1–100 mL / min. In some embodiments, the flow rate of the solution containing the alkaline reagent is 0.1–20 mL / min. In some embodiments, the flow rate of the solution containing the alkaline reagent is 2.0 mL / min.

[0033] In some embodiments, the compound represented by formula (II) or a salt thereof is selected from the compound represented by formula (II-1) or a salt thereof, and the method comprises:

[0034] This disclosure also provides a method for preparing a compound of formula (III) or a salt thereof, comprising the method for preparing a compound of formula (II) or a salt thereof as described in this disclosure, and the steps for preparing a compound of formula (III) or a salt thereof from a compound of formula (II).

[0035] Among them, R 1 Selected from amino protecting groups.

[0036] In some embodiments, the compound represented by formula (III) or a salt thereof is selected from the compound represented by formula (III-1) or a salt thereof, and the method comprises:

[0037] This disclosure also provides a method for preparing a compound of formula (IV) or a salt thereof, including the method for preparing a compound of formula (II) or a salt thereof as described in this disclosure, and / or the method for preparing a compound of formula (III) or a salt thereof as described in this disclosure.

[0038] R1 is selected from amino protecting groups.

[0039] In some embodiments, the compound represented by formula (IV) or a salt thereof is selected from the compound represented by formula (IV-1) or a salt thereof, and the method includes:

[0040] This disclosure also provides a method for preparing a compound of formula (V) or a salt thereof, including at least one of the methods for preparing a compound of formula (II) or a salt thereof, the methods for preparing a compound of formula (III) or a salt thereof, and the methods for preparing a compound of formula (IV) or a salt thereof.

[0041] In some implementations, the method includes:

[0042] This disclosure also provides a method for preparing a compound of formula (B) or a salt thereof, comprising at least one of the methods for preparing a compound of formula (II) or a salt thereof, the methods for preparing a compound of formula (III) or a salt thereof, the methods for preparing a compound of formula (IV) or a salt thereof, and the methods for preparing a compound of formula (V) or a salt thereof.

[0043] The preparation methods disclosed in patents WO2003051840A and WO2010028232A for the compound shown in formula (B) or its salts can be referenced in their entirety here.

[0044] This disclosure also provides a method for preparing a compound of formula (A) or a salt thereof, comprising at least one of the following methods: the method for preparing a compound of formula (II) or a salt thereof, the method for preparing a compound of formula (III) or a salt thereof, the method for preparing a compound of formula (IV) or a salt thereof, the method for preparing a compound of formula (V) or a salt thereof, and the method for preparing a compound of formula (A) or a salt thereof.

[0045] The preparation method of the compound shown in formula (B) or its salt can be referred to the patent disclosed in WO2020259675A, which is cited in its entirety here.

[0046] This disclosure also provides a method for preparing the compound of formula (IV) or a salt thereof, comprising the step of preparing the compound of formula (IV) or a salt thereof from the compound of formula (III).

[0047] R1 is selected from amino protecting groups.

[0048] In some embodiments, the compound of formula (IV) or a salt thereof is selected from the compound of formula (IV-1) or a salt thereof, and the method includes:

[0049] In some embodiments, the preparation method of this disclosure optionally includes a purification step, which includes one or more of column chromatography, solvent slurrying, and recrystallization.

[0050] The salts of the compounds described in this disclosure can be inorganic acid salts and organic acid salts. Inorganic acid salts can be hydrochlorides, sulfates, phosphates, hydrobroms, trifluoroacetates, etc., and organic acids can be formates, acetates, sulfonates, substituted alkyl sulfonates, succinates, maleates, tartrates, citrates, lactates, oxalates, gluconates, fumarates, malonates, malates, etc.

[0051] This disclosure also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (A) prepared according to the above method or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0052] The compound shown in formula (II) or its salt is an important intermediate for rorapitin. Existing technologies (WO2003051840, WO2003042173 and CN106967000A) all employ traditional batch reactors, requiring ultra-low temperatures of -78°C for the reaction. These conditions are harsh, energy-intensive, and costly, hindering large-scale production. This disclosure utilizes a continuous flow microreactor and a catalyst, eliminating the need to lower the temperature to -78°C. This significantly reduces energy consumption, promotes environmental protection and resource conservation, lowers costs, and facilitates subsequent process scale-up.

[0053] Terminology Explanation:

[0054] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0055] In the preparation method described in this disclosure, the reactions connected by "→" all refer to one-step reactions that yield the product.

[0056] "Amino protecting group" is a group known in the art that can be used to protect an amino group, see amino protecting groups in the literature (Protective Groups in Organic Synthesis, 5th Ed. TW Greene & P. ​​GMWuts). Examples include, but are not limited to, urethane protecting groups such as 2-trimethylsilylethoxycarbonyl (Teoc), 1-methyl-1-(4-biphenyl)-ethoxycarbonyl (Bpoc), tert-butoxycarbonyl (BOC), allyloxycarbonyl (Al loc), 9-fluorenylmethyloxycarbonyl (Fmoc), and benzyloxycarbonyl (Cbz); amide protecting groups such as formyl, acetyl, trichloroacetyl, benzoyl, and nitrophenylacetyl; sulfonamide protecting groups such as 2-nitrobenzenesulfonyl; and imine and cyclic imine protecting groups such as phthalimide and dithiosuccinyl.

[0057] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0058] A batch reactor, also known as a turnbuffer reactor, is a type of chemical reactor that performs a discontinuous reaction. During the reaction, reactants, products, and solvents do not flow into or out of the reactor until the target conversion rate is reached. Commonly used batch reactors include, but are not limited to, containers such as reaction flasks or kettles, along with their associated agitators, temperature control equipment, and other necessary devices.

[0059] In the chemical structure of the compounds described in this disclosure, the bonds... This indicates that the configuration is not specified; that is, if chiral isomers exist in the chemical structure, the bond... It can be Or simultaneously include Two configurations. A “pharmaceutical composition” means a mixture containing one or more of the compounds described herein, or their physiologically pharmaceutically acceptable salts or prodrugs, along with other chemical components, such as physiologically pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and its biological activity.

[0060] "Pharmaceutical excipients" include, but are not limited to, any adjuvant, carrier, flow aid, sweetener, diluent, preservative, dye / coloring agent, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that has been approved by the U.S. Food and Drug Administration (FDA) for use in humans or livestock.

[0061] The term "effective amount" or "effective therapeutic amount" as used in this disclosure includes an amount sufficient to improve or prevent symptoms or conditions of a medical condition. An effective amount also means an amount sufficient to allow or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on factors such as the condition to be treated, the patient's overall health, the route and dosage of administration, and the severity of side effects. An effective amount may be the maximum dose or administration regimen that avoids significant side effects or toxicity. Attached Figure Description

[0062] Figure 1: Schematic diagram of the reactor in step 3 of Example 1. Detailed Implementation

[0063] The following detailed explanation of this disclosure will be provided with specific examples to enable those skilled in the art to have a more comprehensive understanding of this disclosure. The specific examples are only used to illustrate the technical solutions of this disclosure and do not limit this disclosure in any way.

[0064] Example 1

[0065] Step 1: Preparation of N-benzyloxycarbonyl-L-2-phenylglycine (1b)

[0066] Compound 1a (20.0 g, 132.3 mmol) was dissolved in tetrahydrofuran (180 mL) and cooled to [temperature missing]. Sodium hydroxide (15.9 g, 396.9 mmol, 3.0 eq.) was dissolved in 400 mL of water and added dropwise to the above reaction solution. Then, benzyl chloroformate (27.1 g, 158.8 mmol, 1.2 eq.) was added dropwise. After the addition was complete, the mixture was stirred for 10 minutes, the cold bath was removed, and the temperature was allowed to rise naturally to 20-30 °C. The reaction mixture was stirred for 4 hours. The pH of the reaction solution was adjusted to 1 with 1 M hydrochloric acid, and the mixture was extracted twice with ethyl acetate (100 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Heptane (200 mL) was added to the crude product, and the mixture was stirred. The mixture was filtered, and the filter cake was washed with pre-cooled heptane. The filter cake was collected, dried under reduced pressure, and compound 1b (35.96 g, yield 95.3%) was obtained.

[0067] MS m / z(ESI): 286[M+1] + .

[0068] Step 2: Preparation of (2R,4S)-5-oxo-2,4-diphenyloxazolidine-3-carboxylic acid benzyl ester (I-1)

[0069] Compound 1b (5.0 g, 17.5 mmol, 1.0 eq) was dissolved in boron trifluoride diethyl ether (42.5 g, 8.5X). Benzaldehyde dimethyl acetal (3.2 g, 21.0 mmol, 1.2 eq) was added dropwise while maintaining an internal temperature of 0-5 °C. The reaction mixture was stirred for 20 hours. The reaction solution was cooled, and water (10 mL) was slowly added dropwise to quench the reaction. After the addition was complete, water (25 mL) was added again, and the mixture was stirred for 1 hour. The mixture was filtered, and the filter cake was washed with water. The filter cake was dissolved in dichloromethane (75 mL) and washed three times with water (25 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was added to ethyl acetate (26 mL), heated, and stirred. After cooling, stirring was continued. The mixture was filtered, and the filter cake was washed with cold ethyl acetate. The filter cake was collected, dried under reduced pressure, and compound I-1 (4.82 g, yield 73.7%) was obtained.

[0070] MS m / z(ESI): 374[M+1] + .

[0071] Step 3: Preparation of (2R,4S)-4-(((R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy)methyl)-5-oxo-2,4-diphenyloxazolidine-3-carboxylic acid benzyl ester (II-1)

[0072] The fluid chemical reaction apparatus was constructed as shown in Figure 1. The precooling ring and tubular reactor were cooled to -30°C. At room temperature, a solution of I⁻ (27.0 g, 72.31 mmol) in dichloromethane (720 mL) was prepared and connected to plunger pump A at a flow rate of 5.0 mL / min. A solution of 0.5 M bis(trimethylsilyl)aminolithium in tetrahydrofuran (290 mL, 2.0 eq) was connected to peristaltic pump B at a flow rate of 2.0 mL / min. A solution of I'⁻ (30.46 g, 86.77 mmol, 1.2 eq) and tetrabutylammonium iodide (13.35 g, 36.15 mmol, 0.5 eq) in dichloromethane (720 mL) was prepared and connected to plunger pump C at a flow rate of 5.0 mL / min. The first retention time was 1.87 min, and the second retention time was 12.5 min. The eluent was collected in a 2L three-necked flask under nitrogen protection, with the internal temperature controlled at -30 to -35°C. After collection, the flask was stirred for 5 minutes. The purity was controlled at 92.0% by HPLC. The eluent was quenched with 2 / 3 saturated ammonium chloride aqueous solution (270 mL), heated to room temperature, stirred, separated, washed with saturated sodium chloride aqueous solution (810 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 10 / 1) to obtain compound II-1 (41.8 g, yield 90.0%).

[0073] 1H NMR (400MHz, CDCl3): δ7.72 (s, 1H), 7.65 (s, 2H), 7.45-7.02 (m, 13H), 6.89-6.87 (d, J = 8.0Hz, 2H), 6.61-6. 53(m,1H),5.04-4.78(dd,J=6.0Hz,2H),4.58-4.32(m,2H),4.06-4.01(m,1H),1.41-1.40(d,J=4.0Hz,3H).

[0074] MS m / z(ESI): 644[M+1] + .

[0075] Step 4: Preparation of (2R,4S)-4-(((R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy)methyl)-5-hydroxy-2,4-diphenyloxazolidine-3-carboxylic acid benzyl ester (III-1):

[0076] Compound II-1 (41.8 g, 65.0 mmol, 1.0 eq.) and dichloromethane (418 mL) were added to a three-necked flask under nitrogen protection and cooled to an internal temperature of -25 to -15 °C. A 1.5 M solution of diisobutylaluminum hydride in toluene (86.7 mL, 130 mmol, 2.0 eq.) was added dropwise. After the addition was complete, the mixture was stirred for 1.5 hours. The internal temperature was kept below 0 °C, and a 30% sodium potassium tartrate aqueous solution (420 mL) was slowly added to quench the reaction. The mixture was heated to room temperature, and dichloromethane (270 mL) and water (270 mL) were added. The mixture was stirred for 20 min. After standing, the mixture was separated, washed with a semi-saturated sodium chloride aqueous solution (836 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Acetic acid (324 mL) was added to the crude product, and the mixture was heated and stirred until dissolved. After cooling, water (216 mL) was added dropwise and stirred. The mixture was then filtered, and the filter cake was rinsed with 50% acetic acid aqueous solution and purified water. The mixture was dried under reduced pressure to obtain compound III-1 (36.0 g, yield 86.0%).

[0077] 1 H NMR (400MHz, CDCl3): δ7.80-7.75(m,3H),7.43-7.16(m,13H),6.84-6.82(d,J=8.0Hz,2H),6.33(s,1H),5.85-5.83(d,J=8.0Hz,1H),5.55(s ,1H),5.00-4.97(d,J=12.0Hz,1H),4.81-4.78(d,J=12.0Hz,1H),4.65(s,1H),4.36(s,1H),4.19-4.17(m,1H),1.54-1.52(d,J=8.0Hz,3H).

[0078] MS m / z(ESI): 646 [M+1] + .

[0079] Step 5: Preparation of (1S)-1-(((1R)-1-[3,5-bis(trifluoromethyl)phenyl)ethoxy)methyl)-1-phenylprop-2-enyl]amine (IV-1):

[0080] In a three-necked flask, add methyltriphenylphosphine bromide (25.5 g, 71.25 mmol, 2.3 eq) and toluene (40 mL), and stir under nitrogen protection. Cool to -15 °C, and add dropwise a 2 M sodium bis(trimethylsilyl)amino sodium solution in tetrahydrofuran (35.6 mL, 71.25 mmol, 2.3 eq). After the addition is complete, stir the reaction for 1 hour. Then, add a toluene solution of compound III-1 (20.0 g, 30.98 mmol, 1.0 eq) in 240 mL to the above reaction system dropwise, completing the addition in about 20 minutes. After the addition is complete, allow the temperature to rise naturally to 20-30 °C, and stir the reaction for 2 hours. Cool the reaction solution, and quench the reaction by adding dropwise 6% aqueous acetic acid solution (160 mL). After the addition is complete, warm to room temperature and allow to stand for separation. The organic phase was washed three times sequentially with a mixed solvent (80 mL, 14% sodium bisulfite and 7% acetic acid aqueous solution), followed by washing with water (160 mL), saturated sodium bicarbonate solution (160 mL), and saturated saline solution (160 mL). The solution was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Toluene (200 mL) was added, stirred to dissolve, and anhydrous magnesium chloride (14.75 g, 154.90 mmol, 5.0 eq) was added, followed by stirring for 16 hours. The solution was filtered, and the filter cake was washed with toluene, with the filtrate concentrated under reduced pressure. Toluene (80 mL) was added, stirred to dissolve, and silica gel (20 g) was added, followed by stirring for 2 hours. The solution was filtered, and the filter cake was washed with toluene, with the filtrate collected. Toluene (40 mL) was added to the silica gel in the filter cake, and the mixture was slurried for 10-15 min. The mixture was filtered, washed with toluene (20 mL), and the toluene slurry was repeated four times. All filtrates were collected and concentrated under reduced pressure to obtain a crude solution (80 mL) of compound IV-1, which was then directly used for the next step.

[0081] MS m / z(ESI): 538 [M+1] + .

[0082] Step 6: Preparation of [(1S)-1-(((1R)-1-[3,5-bis(trifluoromethyl)phenyl)ethoxy)methyl)-1-phenylprop-2-enyl]amine monomaleate (V-1):

[0083] Add 80 mL of the crude solution of compound IV-1 obtained in the previous step to a three-necked reaction flask. Under nitrogen protection, cool to -15°C to -10°C and add trimethyliodosilane (8.06 g, 40.27 mmol, 1.3 eq) dropwise. After the addition is complete, stir the reaction for 2–4 hours. Controlling the internal temperature at -10°C, add methanol (4.96 g, 154.90 mmol) dropwise to quench the reaction, and stir for 1 hour. Add 80 mL of saturated sodium bicarbonate aqueous solution. Heat to room temperature and allow to stand for phase separation. Wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, filter, and obtain toluene filtrate.

[0084] Controlling the internal temperature at 20℃-30℃, a methanol (10 mL) solution of maleic acid (3.6 g, 30.98 mmol, 1.0 eq) was added dropwise to the above toluene solution, and the mixture was stirred for 1-2 hours. The reaction solution was concentrated under reduced pressure. Toluene (20 mL) was added, and the mixture was heated to 35-40℃. Heptane (20 mL) was slowly added dropwise. After the addition was complete, the mixture was stirred for 30 min. The temperature was lowered, and heptane (100 mL) was slowly added dropwise. After the addition was complete, the mixture was stirred for 16-20 hours. The mixture was filtered, and the filter cake was washed successively with a toluene / heptane (V / V = 1 / 6) mixture (20 mL), heptane, and water. The filter cake was collected and dried under reduced pressure to obtain the crude product. The crude product was recrystallized from ethyl acetate / heptane to obtain compound V-1 (13 g).

[0085] 1 H NMR (400MHz, CDCl3): δ7.78(s,1H),7.62-7.61(d,J=4.0Hz,2H),7.43-7.35(m,5H),6.18-6.11(m,3H),5.49-5.46(d,J=12.0Hz,1H), 5.38-5.33(d,J=20.0Hz,1H),4.70-4.65(dd,J=8.0Hz,1H),4.01-3.98(d,J=12.0Hz,1H),3.88-3.85(d,J=12.0Hz,1H),1.45(s,3H).

[0086] MS m / z(ESI): 404[M+1] + .

[0087] Example 2

[0088] Based on step 3 of Example 1, compound II-1 was prepared under different conditions, with the purity controlled as shown in Table 1.

[0089] Table 1. Continuous flow reactions under different conditions

[0090] *V represents the ratio of solvent volume to the mass of compound I-1. For example, if the mass of I-1 is 1g, 10V represents 10 mL.

[0091] Example 3

[0092] Referring to the synthesis method of compound 2 in step 2 of Example 1a / 1b of WO2003051840A, a tetrahydrofuran solution of bis(trimethylsilyl)aminolithium was added to compound I-1 at -65°C, stirred, and then compound I'-1 was added and stirred to react. The intermediate controlled purity under different conditions is as follows.

[0093] Since this disclosure has been described in accordance with its specific implementation, certain modifications and equivalent variations will be apparent to those skilled in the art and are included within the scope of this disclosure.

Claims

1. A method for preparing a compound of formula (II) or a salt thereof, comprising the steps of reacting a solution containing a compound of formula (I) or a salt thereof with a solution containing a catalyst and a compound of formula (I') or a salt thereof, and a solution containing an alkaline reagent in a continuous flow microreactor to prepare a compound of formula (II) or a salt thereof. in, R 1 X is selected from amino protecting groups; X is selected from halogens.

2. The preparation method according to claim 1, wherein the preparation method comprises: 1) The step of mixing and reacting a solution containing the compound of formula (I) or its salt with a solution containing a base reagent. 2) The step of mixing the above reaction solution with a solution containing a catalyst and the compound of formula (I') or its salt.

3. The preparation method according to claim 1 or 2, wherein the amino protecting group is selected from acetyl, methoxyacetyl, trifluoroacetyl, trichloroacetyl, neopentanoyl, formyl, benzoyl, phthaloyl, 9-fluorenylmethoxycarbonyl, tert-butoxycarbonyl and benzyloxycarbonyl.

4. The preparation method according to any one of claims 1-3, wherein the alkali reagent is selected from organoalkali metal reagents; The preferred alkaline reagent is selected from organolithium, sodium, potassium, rubidium, and cesium reagents. More preferably, the base reagent is selected from lithium bis(trimethylsilyl)amino (LiHMDS), sodium bis(trimethylsilyl)amino (NaHMDS), potassium bis(trimethylsilyl)amino (KHMDS), lithium diisopropylamino (LDA), lithium 2,2,6,6-tetramethylpiperidine (TMPLi), lithium tert-butoxide (t-BuOLi), sodium tert-butoxide (t-BuONa), and potassium tert-butoxide (t-BuOK).

5. The preparation method according to any one of claims 1-4, wherein the catalyst is selected from iodide catalysts, bromide catalysts, and chloride catalysts; The preferred catalyst is selected from iodide catalysts; More preferably, tetrabutylammonium iodide (TBAI), lithium iodide (LiI), sodium iodide (NaI), potassium iodide (KI), cuprous iodide (CuI), tetrabutylphosphine iodide, tetrabutylammonium bromide (TBAB), and tetrabutylchloride (TBAC).

6. The preparation method according to any one of claims 1-5, wherein the flow rate of the solution containing the compound of formula (I) or its salt is 0.1-5000 mL / min; preferably 0.1-100 mL / min; more preferably 0.1-20 mL / min.

7. The preparation method according to any one of claims 1-6, wherein the flow rate of the solution containing the catalyst and the compound of formula (I') or its salt is 0.1-5000 mL / min; preferably 0.1-100 mL / min; more preferably 0.1-20 mL / min.

8. The preparation method according to any one of claims 1-7, wherein the flow rate of the solution containing the alkaline reagent is 0.1-5000 mL / min; preferably 0.1-100 mL / min; more preferably 0.1-20 mL / min.

9. A method for preparing a compound of formula (III) or a salt thereof, comprising the method for preparing a compound of formula (II) or a salt thereof as described in any one of claims 1-8, and the step of preparing a compound of formula (III) or a salt thereof from a compound of formula (II). in, R1 is selected from an amino protecting group.

10. A method for preparing a compound of formula (IV) or a salt thereof, comprising the method for preparing a compound of formula (II) or a salt thereof as described in any one of claims 1-8, and / or the method for preparing a compound of formula (III) or a salt thereof as described in claim 9. in, R 1 Selected from amino protecting groups.

11. A method for preparing a compound of formula (V) or a salt thereof, comprising at least one of the methods for preparing a compound of formula (II) or a salt thereof according to any one of claims 1-8, the method for preparing a compound of formula (III) or a salt thereof according to claim 9, or the method for preparing a compound of formula (IV) or a salt thereof according to claim 10.

12. The preparation method according to claim 11, wherein the preparation method comprises:

13. A method for preparing a compound of formula (B) or a salt thereof, comprising at least one of the following methods: the method for preparing a compound of formula (II) or a salt thereof according to any one of claims 1-8; the method for preparing a compound of formula (III) or a salt thereof according to claim 9; the method for preparing a compound of formula (IV) or a salt thereof according to claim 10; or the method for preparing a compound of formula (V) or a salt thereof according to claim 11.

14. A method for preparing a compound of formula (A) or a salt thereof, comprising at least one of the following methods: the method for preparing a compound of formula (II) or a salt thereof according to any one of claims 1-8; the method for preparing a compound of formula (III) or a salt thereof according to claim 9; the method for preparing a compound of formula (IV) or a salt thereof according to claim 10; the method for preparing a compound of formula (V) or a salt thereof according to claim 11; or the method for preparing a compound of formula (A) or a salt thereof according to claim 13.

15. A method for preparing a compound of formula (IV) or a salt thereof, comprising the step of preparing a compound of formula (IV) or a salt thereof from a compound of formula (III), in, R1 is selected from an amino protecting group.

Images