Preparation method of rafenasin intermediate and rafenasin

Abstract

The invention relates to a preparation method of a rafenasin intermediate and rafenasin. The preparation method of the rafenasin intermediate (compound III) comprises the step of carrying out substitution reaction on piperidine-4-yl [1, 1-biphenyl]-2-carbamate (compound I) serving as a raw material and a compound II to obtain the compound III: in the compound II, X is halogen such as chlorine, bromine or iodine. The preparation method of the rafenasin intermediate is simple in reaction principle, few in by-products and simple in post-treatment, and the prepared intermediate is relatively high in yield and relatively good in purity.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical synthesis technology, specifically relating to a refennaxine intermediate and a method for preparing refennaxine. Background Technology

[0002] Rafenasine is a long-acting muscarinic antagonist administered via inhalation solution to improve lung function, reduce clinical symptoms of chronic obstructive pulmonary disease (COPD), and prevent further disease progression. On November 13, 2017, Theravance Biopharmaceuticals submitted a New Drug Application (NDA) to the U.S. FDA for the treatment of COPD in adults, and it was approved on November 9, 2018.

[0003] The structure of refinasine is shown below:

[0004]

[0005] Patent applications CN1759108A, CN1882556A, CN1930125A, CN102958916A, US20050203133A1 and literature J.Med.Chem., 2015, 58(6), 2609-2622 disclose the synthetic route of refennaxine, as shown in Route 1:

[0006] Route 1

[0007]

[0008] This route uses 2-biphenyl isocyanate as a raw material, and proceeds through esterification, hydrogenation, reductive amination, hydrogenation, condensation, and reductive amination to finally obtain refennaxine. The third step of this route uses benzyloxycarbonylmethyl (2-oxoethyl) carbamate, which has low purity, is expensive, and is rarely available commercially. Its reaction with compound 4 produces various impurities, resulting in compound 6 with low purity and difficulty in purification. Therefore, the purity and yield of the prepared product are low, making this route unsuitable for industrial production.

[0009] Patent application CN102958916A reports a synthesis method using N-methylacetal as a starting material, involving acylation, deprotection, reductive amination, hydrogenation, condensation, and reductive amination to obtain the product refennaxine. The synthesis is shown in route 2.

[0010] Route 2

[0011]

[0012] The disadvantages of this route are long reaction time, low yield, and difficulty in cost control; multiple intermediates are oily substances that are difficult to separate, and the process has poor stability, making it difficult to scale up.

[0013] Patent application CN113121416A reports a synthesis of refennaxine from methyl p-formylbenzoate as a starting material via reductive amination, hydrolysis, condensation, deprotection, and reductive amination. The synthesis is shown in route 3.

[0014] Route 3

[0015]

[0016] The disadvantages of this route are that the intermediates after hydrolysis have poor solubility, high inorganic salt residue, difficult purification, low overall yield, and are not suitable for industrial production.

[0017] Patent CN1930125A reports a synthesis method using biphenyl-2-isocyanate as a starting material, reacting it with 4-hydroxy-N-benzylpiperidine via esterification to obtain compound C, compound D via oxidation to obtain compound E, compound C and compound E via reductive amination to obtain compound F, followed by hydrogenation to obtain compound G, compound G and compound H via condensation to obtain compound I, and compound I via reductive amination with compound J to obtain the final product, refennaxine. The synthesis is shown in route 4.

[0018] Route 4:

[0019]

[0020] The disadvantages of this route are: the reaction route is relatively long; the purity of compound E prepared by the oxidation reaction is low and it is not easy to purify; HOBT is used in the preparation of compound I, which is not easy to remove and has a high risk of residue in the finished product; the entire route uses two palladium-carbon hydrogenation reactions, which makes the overall production cost high and is not suitable for industrial production. Summary of the Invention

[0021] To address the shortcomings of existing technologies, this application provides a refennaxine intermediate and a method for preparing refennaxine. The method for preparing the refennaxine intermediate of this invention features a simple reaction principle, few byproducts, and simple post-processing, resulting in a high yield and good purity of the prepared intermediate. The method for preparing refennaxine of this invention has a high overall reaction yield and good purity, does not use highly toxic reagents that are difficult to remove in post-processing, and the production cost of refennaxine prepared by this route is low, making it suitable for industrialized production.

[0022] On the one hand, the present invention provides a method for preparing a revanasine intermediate (i.e., compound III).

[0023]

[0024] The preparation method includes the following steps: using piperidine-4-yl[1,1-biphenyl]-2-carbamate (compound I) as a raw material, and reacting it with compound II through a substitution reaction to obtain compound III:

[0025]

[0026] In compound II, X is a halogen, such as chlorine, bromine, or iodine.

[0027] Preferably, the substitution reaction is carried out in the presence of an acid-binding agent.

[0028] Preferably, the acid-binding agent is selected from one or more of sodium carbonate, potassium carbonate, potassium bicarbonate, triethylamine, pyridine, triethylenediamine, diisopropylethylamine, and N-methylmorpholine, with triethylamine being the most preferred.

[0029] Preferably, the substitution reaction is carried out in the presence of a first organic solvent.

[0030] Preferably, the first organic solvent is selected from one or more of chloroform, tetrahydrofuran, acetonitrile, toluene, 2-methyltetrahydrofuran, 1,4-dioxane, and ethyl acetate, with chloroform being the most preferred.

[0031] Preferably, the molar ratio between the acid-binding agent and compound I is (2-5):1, more preferably (2-3):1.

[0032] Preferably, the molar ratio between compound II and compound I is (1-5):1, more preferably (2-3):1.

[0033] Preferably, the reaction temperature of the substitution reaction is 50°C to 70°C.

[0034] Preferably, the reaction time of the substitution reaction is 8h-20h.

[0035] Preferably, the preparation method further includes the steps of extracting, washing, concentrating, recrystallizing, filtering and drying the obtained compound III.

[0036] Preferably, the recrystallization is carried out in the presence of a second organic solvent.

[0037] Preferably, the second organic solvent is selected from one or more of ethanol, acetonitrile, ethyl acetate, isopropanol, and 1,4-dioxane.

[0038] In the preparation method of refennaxine intermediate of the present invention, compound II is used to replace the aldehyde compound E of the prior art, and compound III is prepared by substitution reaction. The acid-binding agent is, for example, triethylamine. After post-treatment, compound III is obtained by extraction, washing, concentration, recrystallization, filtration and drying. This step is simple to operate, the yield and purity of the prepared intermediate are high, there are few impurities, the material state is good, and the refennaxine product prepared according to the process has good quality and high yield.

[0039] In the preparation method of the refinasine intermediate of the present invention, the amino protecting group of compound II is protected by benzyl. Compared with the Cbz protecting group, the conditions required for removing the benzyl protecting group are milder, the reaction is faster, and the post-processing is simpler.

[0040] On the other hand, the present invention provides a method for preparing revanosin, the method comprising the following steps:

[0041] (1) Compound III undergoes a hydrogenation reaction to yield compound IV;

[0042]

[0043] (2) Compound IV obtained in step (1) and compound V were subjected to a condensation reaction to obtain compound VI;

[0044]

[0045] (3) Compound VI obtained in step (2) is subjected to a reductive amination reaction with compound VII to obtain refennaxine.

[0046]

[0047] Compound III was prepared by the aforementioned method.

[0048] Preferably, in step (1), compound III is dissolved in a third organic solvent, a catalyst is added, and a hydrogenation reaction is carried out. After the reaction is completed, a fourth organic solvent is added for purification, and the mixture is cooled and stirred to obtain compound IV.

[0049] Preferably, in step (1), the third organic solvent is selected from one or more of ethanol, acetic acid, methanol, tetrahydrofuran, ethyl acetate, and 2-methyltetrahydrofuran.

[0050] Preferably, in step (1), the catalyst is selected from one or more of palladium on carbon, Raney nickel, platinum on carbon, and rhodium tri(triphenylphosphine)chloride.

[0051] Preferably, in step (1), the amount of catalyst used is 2% to 30% of the mass of compound III.

[0052] Preferably, in step (1), the reaction temperature of the hydrogenation reaction is 40°C to 65°C.

[0053] Preferably, in step (1), the reaction time of the hydrogenation reaction is 2h-8h.

[0054] Preferably, in step (1), the fourth organic solvent is selected from one or more of ethanol, methanol, ethyl acetate, isopropyl acetate, and acetone.

[0055] Preferably, in step (1), the temperature at which the fourth organic solvent is added and then cooled and stirred is 0°C to 40°C.

[0056] Preferably, in step (2), the molar ratio of compound IV to compound V is 1:1.0 to 1:3.0.

[0057] Preferably, in step (2), compound IV obtained in step (1) is condensed with compound V in a fifth organic solvent under condensing agent conditions. After the reaction is completed, compound VI is prepared by extraction and washing with alkaline solution, concentration, and recrystallization.

[0058] Preferably, in step (2), the fifth organic solvent is selected from one or more of isopropyl acetate, ethyl acetate, dichloromethane, chloroform, acetone, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, and dimethyl sulfoxide.

[0059] Preferably, in step (2), the condensing agent is selected from one or more of DCC / DMAP, CDI, HATU, HBTU, DMTMM, and EDCI / HOBt.

[0060] Preferably, in step (2), the reaction temperature of the condensation reaction is 10℃~40℃.

[0061] Preferably, in step (2), the reaction time of the condensation reaction is 3h to 10h.

[0062] Preferably, in step (2), the alkaline solution is selected from one or more of sodium hydroxide solution, potassium hydroxide solution, sodium bicarbonate solution, and sodium carbonate solution.

[0063] Preferably, in step (2), the solvent used for recrystallization is selected from one or more of ethanol, methanol, acetonitrile, acetone, n-heptane, methyl tert-butyl ether, isopropyl ether, N,N-dimethylformamide, and dimethyl sulfoxide.

[0064] Preferably, in step (3), compound VI obtained in step (2) and compound VII are subjected to a reducing amination reaction in the presence of a sixth organic solvent and a reducing agent to obtain refennaxine;

[0065] Preferably, in step (3), the sixth organic solvent is selected from one or more of dichloromethane, chloroform, methanol, ethanol, toluene, acetone, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, and dimethyl sulfoxide.

[0066] Preferably, in step (3), the molar ratio of compound VI to compound VII is 1:1.0 to 1:5.0.

[0067] Preferably, in step (3), the reducing agent is selected from one or more of sodium borohydride, sodium cyanoborohydride, lithium borohydride, zinc borohydride, lithium aluminum hydride, sodium triacetoxyborohydride, sodium tri(trifluoroacetyl)borohydride, and triethylsilane.

[0068] Preferably, in step (3), the molar ratio between compound VI and the reducing agent is 1:2.5 to 1:5.5.

[0069] Preferably, in step (3), the reaction temperature of the reductive amination reaction is 10°C to 30°C.

[0070] Preferably, in step (3), the reaction time of the reductive amination reaction is 3h to 10h.

[0071] Preferably, step (3) further includes the steps of extracting, washing, concentrating, and recrystallizing the obtained revannasine.

[0072] Preferably, in step (3), the solvent used for recrystallization is selected from one or more of ethanol, methanol, acetonitrile, acetone, n-heptane, methyl tert-butyl ether, isopropyl ether, N,N-dimethylformamide, and dimethyl sulfoxide, with acetone being the most preferred.

[0073] In one specific embodiment, the method for preparing revanasine according to the present invention includes the following steps:

[0074] Using piperidine-4-yl[1,1-biphenyl]-2-carbamate (compound I) as a starting material, compound III was obtained by a substitution reaction with compound II;

[0075] The obtained compound III was subjected to a hydrogenation reaction to obtain compound IV;

[0076] The obtained compound IV and compound V were subjected to a condensation reaction to obtain compound VI;

[0077] The obtained compound VI was subjected to a reductive amination reaction with compound VII to obtain refennacine.

[0078] The synthesis route is as follows:

[0079]

[0080] Substitution reaction: Piperidin-4-yl[1,1-biphenyl]-2-carbamate (compound I) reacted with compound II and triethylamine in chloroform at 60℃~70℃ for 12~16h. After the reaction was completed, the mixture was cooled to room temperature, water was added and stirred, extracted, washed, and the organic phase was concentrated. The concentrated residue was added to ethanol for recrystallization, filtered, and dried to obtain compound III.

[0081] Hydrogenation reaction: Compound III and 10% palladium on carbon were reacted in ethanol under a hydrogen atmosphere at 40℃~50℃ for 4~7h. The mixture was filtered, the filtrate was concentrated, the concentrated residue was purified with ethyl acetate, cooled and stirred, filtered, and dried to obtain compound IV.

[0082] Condensation reaction: Compound IV, p-formylbenzoic acid (compound V), and DMTMM were reacted in ethyl acetate at 20℃~30℃ for 3~6h. After the reaction was completed, sodium hydroxide solution was added for extraction, washing, concentration, recrystallization with acetone, filtration, and drying to obtain compound VI.

[0083] Reductive amination reaction: Compound VI and 4-piperidinecarboxamide (compound VII) and sodium triacetoxyborohydride were reacted in chloroform at 10℃~30℃ for 3~6h. After the reaction was completed, the mixture was filtered, purified water was slowly added, and the mixture was extracted, separated, and the organic phase was washed twice with water. The organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The concentrated residue was recrystallized with acetone, filtered, and dried to obtain rafenacin.

[0084] Compared with the prior art, this application has at least the following beneficial technical effects.

[0085] This application provides a novel synthetic route for the intermediate compound III of refennaxine, wherein the amino protecting group of compound II is protected by benzyl. Compared with the Cbz protecting group, the removal of the benzyl protecting group requires milder conditions, faster reaction, and simpler post-processing.

[0086] This application also provides a method for preparing refennaxine using the above-mentioned intermediate, which has the advantages of high yield, convenient operation and suitability for industrial production.

[0087] The beneficial effects of adopting the above-mentioned technical solution of the present invention are as follows:

[0088] The method provided by this invention uses triethylamine in the substitution reaction, controls the feed ratio and post-processing method, reduces the generation of by-products, and greatly improves the purity and yield. The purity can reach more than 99.5% and the yield can reach more than 80%.

[0089] The hydrogenation reaction of this invention, by adjusting parameters such as solvent, reaction temperature, and catalyst dosage, reduces byproducts, achieves a purity of over 99.5%, and a yield of over 90%.

[0090] The condensation reaction of this invention, by adjusting conditions such as solvent, feed ratio, reaction temperature, and post-treatment purification method, reduces byproducts, produces compound VI in good condition, and achieves a yield of up to 90%.

[0091] This invention provides a method for preparing refennaxine with high yield and high purity. The method has fewer steps, low impurity content in the product, purity of over 99.9%, and total yield of over 50%, making it suitable for industrial-scale production. Attached Figure Description

[0092] Figure 1 The hydrogen spectrum of refennacetin;

[0093] Figure 2 The carbon spectrum of refennaxine;

[0094] Figure 3 This is the HPLC chromatogram of refenapyridine. Detailed Implementation

[0095] The present invention will be further described below with reference to embodiments, which are as follows:

[0096] Example 1: Preparation of Compound III

[0097] 75.0 g of chloroform was added to the reaction flask, and stirring was started. 14.86 g (67.5 mmol) of N-(2-chloroethyl)-N-methylbenzylamine hydrochloride (MW: 220.14) and 17.07 g (168.7 mmol) of triethylamine were added. The temperature was raised to 30℃~40℃ and stirred for 0.5 h. 10.00 g (33.7 mmol) of piperidin-4-yl[1,1-biphenyl]-2-carbamate was added, and the reaction was carried out at 60℃~70℃ for 12 h. After the reaction was complete, the reaction solution was cooled to 20℃~30℃, and 50g of purified water was added to wash and extract the liquid. The organic phase was concentrated under reduced pressure. 60.0g of isopropanol was added to the concentrated residue, and the mixture was heated to 50℃~60℃ and stirred for 0.5h. The mixture was then cooled to 0℃~10℃ and stirred for 1h. The mixture was filtered, and the filter cake was dried under vacuum at 45℃~55℃. The product was collected to obtain 12.77g of compound III, with a yield of 85.3% and a purity of 99.6%.

[0098] Example 2: Preparation of Compound III

[0099] 75.0 g of chloroform was added to the reaction flask, and stirring was started. 17.86 g (81.1 mmol) of N-(2-bromoethyl)-N-methylbenzylamine hydrochloride and 17.07 g (168.7 mmol) of triethylamine were added. The temperature was raised to 30℃~40℃ and stirred for 0.5 h. 10.00 g (33.7 mmol) of piperidine-4-yl[1,1-biphenyl]-2-carbamate was added, and the reaction was carried out at 60℃~70℃ for 12 h. After the reaction was complete, the reaction solution was cooled to 20℃~30℃, and 50g of purified water was added to wash and extract the liquid. The organic phase was concentrated under reduced pressure. 60.0g of isopropanol was added to the concentrated residue, and the mixture was heated to 50℃~60℃ and stirred for 0.5h. The mixture was then cooled to 0℃~10℃ and stirred for 1h. The mixture was filtered, and the filter cake was dried under vacuum at 45℃~55℃. The product was collected to obtain 12.39g of compound III, with a yield of 82.8% and a purity of 99.4%.

[0100] Example 3: Preparation of Compound III

[0101] Add 75.0 g of tetrahydrofuran to the reaction flask, start stirring, add 14.86 g (67.5 mmol) of N-(2-fluoroethyl)-N-methylbenzylamine hydrochloride and 17.07 g (168.7 mmol) of triethylamine, heat to 30℃~40℃ and stir for 0.5 h, add 10.00 g (33.7 mmol) of piperidin-4-yl[1,1-biphenyl]-2-carbamate, and react at 60℃~70℃ for 12 h. After the reaction was complete, the reaction solution was cooled to 20℃~30℃, and 50g of purified water was added to wash and extract the liquid. The organic phase was concentrated under reduced pressure. 60.0g of isopropanol was added to the concentrated residue, and the mixture was heated to 50℃~60℃ and stirred for 0.5h. The mixture was then cooled to 0℃~10℃ and stirred for 1h. The mixture was filtered, and the filter cake was dried under vacuum at 45℃~55℃. The product was collected to obtain 10.87g of compound III, with a yield of 72.4% and a purity of 99.5%.

[0102] Example 4: Preparation of Compound III

[0103] 75.0 g of chloroform was added to the reaction flask, and stirring was started. 14.86 g (67.5 mmol) of N-(2-chloroethyl)-N-methylbenzylamine hydrochloride and 23.31 g (168.7 mmol) of potassium carbonate were added. The temperature was raised to 30℃~40℃ and stirred for 0.5 h. 10.00 g (33.7 mmol) of piperidin-4-yl[1,1-biphenyl]-2-carbamate was added, and the reaction was carried out at 60℃~70℃ for 12 h. After the reaction was complete, the reaction solution was cooled to 20℃~30℃, and 50g of purified water was added to wash and extract the liquid. The organic phase was concentrated under reduced pressure. 60.0g of isopropanol was added to the concentrated residue, and the mixture was heated to 50℃~60℃ and stirred for 0.5h. The mixture was then cooled to 0℃~10℃ and stirred for 1h. The mixture was filtered, and the filter cake was dried under vacuum at 45℃~55℃. The product was collected to obtain 11.43g of compound III, with a yield of 76.4% and a purity of 98.2%.

[0104] Example 5: Preparation of Compound III

[0105] 11.25 kg of chloroform was added to the reaction flask, and stirring was started. 2.23 kg (10.1 mol) of N-(2-chloroethyl)-N-methylbenzylamine hydrochloride (MW: 220.14) and 2.56 kg (25.3 mol) of triethylamine were added. The temperature was raised to 30℃~40℃ and stirred for 0.5 h. 1.50 g (5.06 mmol) of piperidine-4-yl[1,1-biphenyl]-2-carbamate was added, and the reaction was carried out at 60℃~70℃ for 12 h. After the reaction was complete, the reaction solution was cooled to 20℃~30℃, and 7.50 kg of purified water was added to wash and extract the liquid. The organic phase was concentrated under reduced pressure. The concentrated residue was added to 9.00 kg of isopropanol, heated to 50℃~60℃ and stirred for 0.5 h, cooled to 0℃~10℃ and stirred for 1 h, filtered, and the filter cake was dried under vacuum at 45℃~55℃. The product was collected to obtain 1.97 g of compound III, with a yield of 87.6% and a purity of 99.7%.

[0106] Example 6: Preparation of Compound III (Comparative Example)

[0107]

[0108] Biphenyl-2-isocyanate (compound A) (97.5 g, 521 mmol) and 4-hydroxy-N-benzylpiperidine (compound B) (105 g, 549 mmol) were heated together at 70 °C for 12 hours. The reaction mixture was then cooled to 50 °C and EtOH (1 L) was added, followed by the slow addition of 6 M HCl (191 mL). The resulting mixture was then cooled to room temperature and ammonium formate (98.5 g, 1.56 mol) was added, followed by bubbling of the solution with nitrogen for 20 minutes. Palladium on activated carbon (20 g, 10 wt.% dry basis) was then added, and the reaction mixture was heated at 40 °C for 12 hours, followed by filtration through a diatomaceous earth mat. The solvent was then removed under reduced pressure, and 1 MHCl (40 mL) was added to the crude residue. The pH of the mixture was then adjusted to pH 12 with 10 N NaOH. The aqueous layer was extracted with ethyl acetate (2 x 150 mL), and the organic layer (magnesium sulfate) was dried, filtered, and the solvent was removed under reduced pressure to give compound C in 100% yield.

[0109] 30.5 g (184.6 mmol) of N-methyl-N-hydroxyethylbenzylamine and 500 g of dichloromethane were added to a reaction flask. The mixture was cooled to -10 °C to 0 °C, and 87.0 g of sulfur trioxide pyridine was added. The mixture was stirred, extracted, washed, and dried to obtain a dichloromethane solution of compound E. This solution was directly used for the next reaction without purification. 30.0 g (101.2 mmol) of compound C and 45.0 g of sodium triacetoxyborohydride were added to the above reaction solution. The mixture was stirred overnight, then quenched with 1 N hydrochloric acid. The mixture was separated, washed with 1 N sodium hydroxide solution and saturated sodium chloride, and dried with anhydrous magnesium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The concentrated residue was dissolved in a small amount of isopropanol, cooled to crystallize, filtered, and dried to obtain 23.7 g of compound F (i.e., compound III of this invention), with a purity of 62.9% and a yield of 52.8%.

[0110] Structural confirmation of compound III of the present invention in Examples 1-5 (compound F in Example 6): 1 H-NMR, 600MHz, DMSO-d6)δ: 1.404-1.418(d, 2H), 1.693(s, 2H), 2.101-2.127(m, 5H), 1.724(s, 1H), 1.898-1.934(t, 3H), 2.034-2.091(m, 1H) ), 2.214(s, 1H), 2.383(m, 2H), 2.401-2.418(m, 4H), 2.594(d, 2H), 3.4 64(s, 2H), 4.401-4.498(m, 1H), 7.242-7.429(m, 14H), 8.644(s, 1H); ( 13C-NMR, 600MHz, DMSO-d6)δ: 31.30, 42.74, 51.24, 54.96, 56.12, 62.29, 70.65, 126.45, 127.24 ,127.47, 128.28, 128.45, 128.71, 129.09, 129.13, 130.71, 135.28, 137.90, 139.70, 154.41; C 28 H 33 The N3O2 molecular ion peak is represented by MS (ESI): m / z [M+H]. + :444.

[0111] Example 7: Preparation of Compound IV

[0112] 88.0 g of methanol, 11.0 g (24.8 mmol) of compound III (prepared from Example 5) and 0.55 g of palladium on carbon were added to the reaction flask. The mixture was reacted at 40 °C–50 °C for 5 h under a hydrogen atmosphere. After filtration, the filtrate was concentrated to dryness under reduced pressure. 22.0 g of ethyl acetate was added, and the mixture was cooled to 10 °C–20 °C and stirred for 1 h. After filtration, the filter cake was dried under vacuum at 45 °C–55 °C to give 7.96 g of compound IV, with a yield of 90.7% and a purity of 99.6%.

[0113] Example 8: Preparation of Compound IV

[0114] 88.0 g of ethanol, 11.0 g (24.8 mmol) of compound III (prepared in Example 5) and 0.55 g of Raney nickel were added to a reaction flask. The mixture was reacted at 40 °C–50 °C for 5 h under a hydrogen atmosphere. After filtration, the filtrate was concentrated to dryness under reduced pressure. 22.0 g of ethyl acetate was added, and the mixture was cooled to 10 °C–20 °C and stirred for 1 h. After filtration, the filter cake was dried under vacuum at 45 °C–55 °C to give 7.74 g of compound IV, with a yield of 88.2% and a purity of 99.4%.

[0115] Example 9: Preparation of Compound IV

[0116] 88.0 g of ethanol, 11.0 g (24.8 mmol) of compound III (prepared in Example 5) and 0.55 g of palladium on carbon were added to a reaction flask. The reaction was carried out at 40 °C–50 °C for 5 h under a hydrogen atmosphere. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. 22.0 g of ethyl acetate was added, and the mixture was cooled to 10 °C–20 °C and stirred for 1 h. The mixture was filtered, and the filter cake was dried under vacuum at 45 °C–55 °C to give 8.22 g of compound IV, with a yield of 93.7% and a purity of 99.8%.

[0117] Example 10: Preparation of Compound IV

[0118] 88.0 g of ethanol, 11.0 g (24.8 mmol) of compound III (prepared in Example 5) and 1.10 g of palladium on carbon were added to a reaction flask. The mixture was reacted at 40 °C–50 °C for 5 h under a hydrogen atmosphere. After filtration, the filtrate was concentrated to dryness under reduced pressure. 22.0 g of ethyl acetate was added, and the mixture was cooled to 10 °C–20 °C and stirred for 1 h. After filtration, the filter cake was dried under vacuum at 45 °C–55 °C to give 8.30 g of compound IV, with a yield of 94.6% and a purity of 99.7%.

[0119] Example 11: Preparation of Compound IV

[0120] 12.0 kg of ethanol, 1.50 kg (3.38 mol) of compound III (prepared from Example 5) and 75.0 g of palladium on carbon were added to a reaction flask. The reaction was carried out under a hydrogen atmosphere at 40 °C–50 °C for 5 h. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. 3.0 kg of ethyl acetate was added, and the mixture was cooled to 10 °C–20 °C and stirred for 1 h. The mixture was filtered, and the filter cake was dried under vacuum at 45 °C–55 °C to obtain 1.09 kg of compound IV, with a yield of 91.2% and a purity of 99.6%.

[0121] The structure of compound IV in Examples 7-11 was confirmed: 1 H-NMR, 600MHz, DMSO-d6)δ: 1.64-1.65(m, 2H), 1.89-1.92(m, 2H), 2.10(s, 1H), 2.13-2.19(m, 2H), 2.38-2.39(m, 3H), 2.41-2.44(m, 2H), 2.59- 2.61(m, 2H), 2.62-2.67(m, 2H), 4.72(s, 1H), 6.86(s, 1H), 7.11(m, 1H), 7.19-7.21(m, 1H), 7.33-7.39(m, 4H), 7.44-7.47(m, 2H), 8.12(s, 1H); ( 13 C-NMR, 600MHz, DMSO-d6)δ: 31.13, 36.51, 48.98, 51.14, 57.64, 71.43, 120.44, 12 3.55, 127.80, 128.38, 129.02, 129.24, 130.21, 131.95, 134.90, 138.31, 153.27; C 21 H 27 The N3O2 molecular ion peak is represented by MS (ESI): m / z [M+H]. + :354.

[0122] Example 12: Preparation of Compound VI

[0123] 64.0 g of ethyl acetate was added to the reaction flask, and stirring was started. 3.74 g (24.9 mmol) of compound V and 4.30 g (26.5 mmol) of CDI were added, and the mixture was stirred at 20°C–30°C for 0.5 h. Then, 8.0 g (22.6 mmol) of compound IV (prepared in Example 11) was added, and the mixture was reacted at 20°C–30°C for 4 h. After the reaction was complete, the reaction solution was washed with an aqueous sodium hydroxide solution. The organic phase was concentrated to dryness under reduced pressure. 5.6 g of acetone was added to the concentrated residue, and the mixture was heated to 50°C–60°C and stirred for 0.5 h. The mixture was then cooled to 5°C–15°C and stirred for 3 h. The mixture was filtered, and the filter cake was dried under vacuum at 45°C–55°C to obtain 9.05 g of compound VI, with a yield of 82.3% and a purity of 98.2%.

[0124] Example 13: Preparation of Compound VI

[0125] 64.0 g of ethyl acetate was added to the reaction flask, and stirring was started. 3.74 g (24.9 mmol) of compound V and 7.34 g (24.9 mmol) of DMTMM were added, and the mixture was stirred at 20°C–30°C for 0.5 h. Then, 8.0 g (22.6 mmol) of compound IV (prepared in Example 11) was added, and the mixture was reacted at 20°C–30°C for 4 h. After the reaction was complete, the reaction solution was washed with an aqueous sodium hydroxide solution. The organic phase was concentrated to dryness under reduced pressure. 5.6 g of acetone was added to the concentrated residue, and the mixture was heated to 50°C–60°C and stirred for 0.5 h. The mixture was then cooled to 5°C–15°C and stirred for 3 h. The mixture was filtered, and the filter cake was dried under vacuum at 45°C–55°C to obtain 9.94 g of compound VI, with a yield of 90.4% and a purity of 99.2%.

[0126] Example 14: Preparation of Compound VI

[0127] 64.0 g of chloroform was added to the reaction flask, and stirring was started. 3.74 g (24.9 mmol) of compound V and 7.34 g (24.9 mmol) of DMTMM were added, and the mixture was stirred at 20°C–30°C for 0.5 h. Then, 8.0 g (22.6 mmol) of compound IV (prepared in Example 11) was added, and the mixture was reacted at 20°C–30°C for 4 h. After the reaction was complete, the reaction solution was washed with an aqueous sodium hydroxide solution. The organic phase was concentrated to dryness under reduced pressure. 5.6 g of acetone was added to the concentrated residue, and the mixture was heated to 50°C–60°C and stirred for 0.5 h. The mixture was then cooled to 5°C–15°C and stirred for 3 h. The mixture was filtered, and the filter cake was dried under vacuum at 45°C–55°C to obtain 9.30 g of compound VI, with a yield of 84.5% and a purity of 98.6%.

[0128] Example 15: Preparation of Compound VI

[0129] 64.0 g of ethyl acetate was added to the reaction flask, and stirring was started. 3.74 g (24.9 mmol) of compound V and 7.34 g (24.9 mmol) of DMTMM were added, and the mixture was stirred at 20°C–30°C for 0.5 h. Then, 8.0 g (22.6 mmol) of compound IV (prepared in Example 11) was added, and the mixture was reacted at 20°C–30°C for 4 h. After the reaction was complete, the reaction solution was washed with an aqueous potassium hydroxide solution. The organic phase was concentrated to dryness under reduced pressure. 5.6 g of acetone was added to the concentrated residue, and the mixture was heated to 50°C–60°C and stirred for 0.5 h. The mixture was then cooled to 5°C–15°C and stirred for 3 h. The mixture was filtered, and the filter cake was dried under vacuum at 45°C–55°C to obtain 9.88 g of compound VI, with a yield of 89.8% and a purity of 99.1%.

[0130] Example 16: Preparation of Compound VI

[0131] 64.0 g of ethyl acetate was added to the reaction flask, and stirring was started. 3.74 g (24.9 mmol) of compound V and 7.34 g (24.9 mmol) of DMTMM were added, and the mixture was stirred at 20°C–30°C for 0.5 h. Then, 8.0 g (22.6 mmol) of compound IV (prepared in Example 11) was added, and the mixture was reacted at 20°C–30°C for 4 h. After the reaction was complete, the reaction solution was washed with an aqueous sodium hydroxide solution. The organic phase was concentrated to dryness under reduced pressure. 5.6 g of acetonitrile was added to the concentrated residue, and the mixture was heated to 50°C–60°C and stirred for 0.5 h. The mixture was then cooled to 5°C–15°C and stirred for 3 h. The mixture was filtered, and the filter cake was dried under vacuum at 45°C–55°C to obtain compound VI, with a yield of 86.9% and a purity of 98.8%.

[0132] Example 17: Preparation of Compound VI

[0133] 8.0 kg of ethyl acetate was added to the reaction flask, and stirring was started. 0.47 kg (3.11 mol) of compound V and 0.92 kg (3.11 mol) of DMTMM were added, and the mixture was stirred at 20°C–30°C for 0.5 h. Then, 1.0 kg (2.83 mol) of compound IV (prepared from Example 11) was added, and the mixture was reacted at 20°C–30°C for 4 h. After the reaction was complete, the reaction solution was washed with an aqueous sodium hydroxide solution. The organic phase was concentrated to dryness under reduced pressure. 0.7 kg of acetone was added to the concentrated residue, and the mixture was heated to 50°C–60°C and stirred for 0.5 h. The mixture was then cooled to 5°C–15°C and stirred for 3 h. The mixture was filtered, and the filter cake was dried under vacuum at 45°C–55°C to obtain 1.25 kg of compound VI, with a yield of 91.1% and a purity of 99.1%.

[0134] The structure of compound VI in Examples 12-17 was confirmed: 1H-NMR, 600MHz, DMSO-d6)δ: 1.58-1.68(d, 2H), 1.82-1.95(d, 2H), 2.08(s, 1H), 2.23-2.33(d, 1H), 2.41-2.46(m, 2H), 2.63-2.64(d, 1H), 2.94(s, 1H), 3.10(s, 3H), 3.30-3.31(s, 1H), 3.64-3.66(m, 1 H), 4.65-4.68 (d, 1H), 6.61 (s, 1H), 7.10-7.13 (m, 1H), 7.19-7.21 (m, 1H), 7.33-7.36 (m, 3H), 7.39- 7.40 (m, 1H), 7.42-7.49 (m, 2H), 7.53-7.57 (m, 2H), 7.90-7.91 (m, 2H), 8.08 (s, 1H), 10.02 (s, 1H); ( 13 C-NMR, 600MHz, DMSO-d6)δ: 330.96, 31.18, 37.93, 44.97, 51.22, 54.99, 55.95, 119.93, 123.50, 126.67, 127.51, 12 7.91, 128.46, 129.12, 129.28, 129.82, 130.26, 131.65, 134.79, 136.72, 138.17, 142.37, 153.09, 170.08, 191.55; C 29 H 31 The N3O4 molecular ion peak is represented by MS (ESI): m / z [M+H]. + :486.

[0135] Example 18: Preparation of revanasin

[0136] 180.0 g of methanol, 18.0 g of N,N-dimethylacetamide, 4.74 g (37.0 mmol) of compound VII, and 9.0 g (18.5 mmol) of compound VI (prepared from Example 17) were added to a reaction vessel. 2.45 g (64.8 mmol) of sodium borohydride was added at a controlled temperature of 15°C–25°C, and the reaction was maintained at this temperature for 4 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure. 72.0 g of acetone was added to the concentrated residue, and the mixture was heated to 50°C–60°C, then cooled to 0°C–10°C and stirred for 3 h. The mixture was filtered, and the filter cake was dried under vacuum at 45°C–55°C to obtain 7.18 g of refennaxine, with a yield of 72.9% and a purity of 99.5%.

[0137] Example 19: Preparation of Revannacin

[0138] 180.0 g of chloroform, 18.0 g of N,N-dimethylacetamide, 4.74 g (37.0 mmol) of compound VII, and 9.0 g (18.5 mmol) of compound VI (prepared from Example 17) were added to a reaction vessel. 2.45 g (64.8 mmol) of sodium borohydride was added at a controlled temperature of 15°C–25°C, and the reaction was maintained at this temperature for 4 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure. 72.0 g of acetone was added to the concentrated residue, and the mixture was heated to 50°C–60°C, then cooled to 0°C–10°C and stirred for 3 h. The mixture was filtered again, and the filter cake was dried under vacuum at 45°C–55°C to obtain 7.31 g of refennaxine, with a yield of 74.2% and a purity of 99.4%.

[0139] Example 20: Preparation of revanasin

[0140] 180.0 g of chloroform, 18.0 g of N,N-dimethylacetamide, 4.74 g (37.0 mmol) of compound VII, and 9.0 g (18.5 mmol) of compound VI (prepared from Example 17) were added to a reaction vessel. The temperature was controlled at 15°C–25°C, and 13.75 g (64.8 mmol) of sodium triacetoxyborohydride was added. The reaction was maintained at this temperature for 4 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure. 72.0 g of acetone was added to the concentrated residue, and the temperature was raised to 50°C–60°C, then lowered to 0°C–10°C and stirred for 3 h. The mixture was filtered, and the filter cake was dried under vacuum at 45°C–55°C to obtain 8.03 g of refennaxine, with a yield of 81.5% and a purity of 99.9%.

[0141] Example 21: Preparation of revanasin

[0142] 180.0 g of chloroform, 18.0 g of N,N-dimethylacetamide, 2.38 g (18.5 mmol) of compound VII, and 9.0 g (18.5 mmol) of compound VI (prepared from Example 17) were added to a reaction vessel. The temperature was controlled at 15°C–25°C, and 13.75 g (64.8 mmol) of sodium triacetoxyborohydride was added. The reaction was maintained at this temperature for 4 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure. 72.0 g of acetone was added to the concentrated residue, and the temperature was raised to 50°C–60°C, then lowered to 0°C–10°C and stirred for 3 h. The mixture was filtered, and the filter cake was dried under vacuum at 45°C–55°C to obtain 6.91 g of refennaxine, with a yield of 64.8% and a purity of 97.5%.

[0143] Example 22: Preparation of revanasin

[0144] 1.1 kg of chloroform, 18.0 g of N,N-dimethylacetamide, 4.74 g (37.0 mmol) of compound VII, and 9.0 g (18.5 mmol) of compound VI (prepared from Example 17) were added to a reaction vessel. The temperature was controlled at 15°C–25°C, and 9.8 g (46.0 mmol) of sodium triacetoxyborohydride was added. The reaction was maintained at this temperature for 4 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure. 72.0 g of acetone was added to the concentrated residue, and the temperature was raised to 50°C–60°C, then lowered to 0°C–10°C and stirred for 3 h. The mixture was filtered, and the filter cake was dried under vacuum at 45°C–55°C to obtain 7.50 g of refennaxine, with a yield of 76.2% and a purity of 99.7%.

[0145] Example 23: Preparation of revanasin

[0146] 19.6 kg of chloroform, 1.9 kg of N,N-dimethylacetamide, 0.52 kg (4.04 mol) of compound VII, and 0.98 kg (2.02 mol) of compound VI (prepared from Example 17) were added to a reaction vessel. The temperature was controlled at 15°C–25°C, and 1.50 kg (7.07 mol) of sodium triacetoxyborohydride was added. The reaction was maintained at this temperature for 4 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. 7.8 kg of acetone was added to the concentrated residue, and the temperature was raised to 50°C–60°C, then lowered to 0°C–10°C and stirred for 3 hours. The mixture was filtered, and the filter cake was dried under vacuum at 45°C–55°C to obtain 1.01 kg of refennaxine, with a yield of 83.2% and a purity of 99.9%.

[0147] Refinasine structure confirmed: ( 1 H-NMR, 600MHz, DMSO-d6)δ: 1.324-1.457(d, 2H), 1.542-1.588(m, 3H), 1.644-1.662(d, 2H), 1.72 4(s, 1H), 1.898-1.934(t, 3H), 2.034-2.091(m, 1H), 2.214(s, 1H), 2.383(m, 2H), 2.679(s, 1H), 2. 789-2.806(d, 2H), 2.900-2.946(d, 3H), 3.271(s, 1H), 3.344(s, 2H), 3.528(s, 1H), 3.376-3.458(d, 1H), 6.716(s, 1H), 7.205(s, 1H), 7.290-7.356(m, 10H), 7.371-7.428(m, 2H), 8.629(s, 1H), the spectrum is as follows Figure 1 ;( 13C-NMR, 600MHz, DMSO-d6) δ: 29.01, 31.16, 31.34, 42.15, 50.94, 53.21, 62.46, 126.52, 127.09, 127.47, 127.59, 128.30, 128.89, 129.10, 130.71, 135.24, 137.99, 139.72, 154.39, 177.00, spectral values ​​are as follows: Figure 2 C 35 H 43 The N5O4 molecular ion peak is represented by MS (ESI): m / z [M+H]. + : 598; High performance liquid chromatography purity 99.9%, chromatogram is as follows Figure 3 .

[0148] Experimental Example 1: Investigation of Substitution Reactions

[0149] The specific method is the same as the substitution reaction operation in Example 1, except that sodium carbonate, potassium carbonate, potassium bicarbonate, pyridine, and triethylenediamine are used instead of triethylamine as acid-binding agents; the yield and purity of compound III are shown in Table 1:

[0150] Table 1

[0151] name Molecular formula yield purity Triethylamine <![CDATA[C6H 15 N]]> 85.3％ 99.6％ Sodium carbonate <![CDATA[Na2CO3]]> 62.9％ 96.2％ Potassium carbonate <![CDATA[K2CO3]]> 76.4％ 98.2％ Potassium bicarbonate <![CDATA[KHCO3]]> 72.5％ 98.0％ Pyridine <![CDATA[C5H5N]]> 78.1％ 97.7％ Triethylenediamine <![CDATA[C6H 12 N2]]> 80.4％ 98.8％

[0152] Experimental Example 2: Investigation of Substitution Reactions

[0153] The specific method is the same as the substitution reaction operation in Example 3, except that acetonitrile, toluene, 2-methyltetrahydrofuran, 1,4-dioxane, ethyl acetate, and chloroform are used instead of tetrahydrofuran as the reaction solvent. The yield and purity of compound III are shown in Table 2.

[0154] Table 2

[0155] name Molecular formula yield purity chloroform <![CDATA[CHCl3]]> 85.3％ 99.6％ Tetrahydrofuran <![CDATA[C4H8O]]> 72.4％ 99.5％ Acetonitrile <![CDATA[CH3CN]]> 83.7％ 99.3％ Toluene <![CDATA[C7H8]]> 80.7％ 98.9％ 2-Methyltetrahydrofuran <![CDATA[C5H 10 O]]> 75.2％ 99.1％ 1,4-Dioxane <![CDATA[C4H8O2]]> 80.4％ 98.8％ Ethyl acetate <![CDATA[C4H8O2]]> 73.8％ 99.3％

[0156] Experiment Example 3: Investigation of the hydrogenation reaction

[0157] The specific method is the same as the hydrogenation reaction operation in Example 9, except that Raney nickel, platinum on carbon, and rhodium tri(triphenylphosphine)chloride are used instead of palladium on carbon as catalysts. The yield and purity of compound IV are shown in Table 3.

[0158] Table 3

[0159] name Molecular formula yield purity Raney nickel — 88.2％ 99.4％ platinum carbon Pt / C 89.8％ 99.3％ Palladium on carbon Pd / C 93.7％ 99.8％ Tris(triphenylphosphine) rhodium chloride <![CDATA[(RhCl(PPh3)3)]]> 83.3％ 97.2％

[0160] Experiment Example 4: Investigation of the hydrogenation reaction

[0161] The specific method is the same as the hydrogenation reaction operation in Example 9, except that the mass ratio of palladium-on-carbon catalyst to compound III is 0.05:1, 0.10:1, 0.15:1, and 0.20:1. The yield and purity of compound IV are shown in Table 4.

[0162] Table 4

[0163]

[0164]

[0165] Experimental Example 5: Investigation of Condensation Reactions

[0166] The specific method is the same as the condensation reaction operation in Example 13, except that DCC / DMAP, CDI, HATU, HBTU or EDCI / HOBt are used instead of DMTMM as the condensing agent. The yield and purity of compound VI are shown in Table 5.

[0167] Table 5

[0168] name yield purity DCC / DMAP 77.8％ 94.4％ CDI 82.3％ 98.2％ HATU 81.6％ 98.4％ HBTU 83.3％ 98.1％ EDCI / HOBt 74.5％ 92.3％ DMTMM 90.4％ 99.2％

[0169] Experiment Example 6: Investigation of Condensation Reactions

[0170] The specific method is the same as the condensation reaction operation in Example 13, except that the recrystallization solvent is replaced with isopropyl acetate, ethyl acetate, dichloromethane, chloroform, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, or dimethyl sulfoxide instead of acetone. The yield and purity of compound VI are shown in Table 6.

[0171] Table 6

[0172]

[0173]

[0174] Experimental Example 7: Investigation of Reductive Amination Reaction

[0175] The specific method is the same as the reductive amination reaction operation in Example 21, except that the molar ratio of compound VII to compound VI is 1.0:1, 2.0:1, 3.0:1, 4.0:1, and 5.0:1. The yield and purity of refennacetin are shown in Table 7.

[0176] Table 7

[0177] molar ratio of compound VII to compound VI yield purity 1.0:1 64.8％ 97.5％ 2.0:1 81.5％ 99.9％ 3.0:1 80.5％ 99.8％ 4.0:1 77.8％ 99.6％ 5.0:1 78.2％ 99.6％ .

Claims

1. A method for preparing a revanasine intermediate (i.e., compound III), The preparation method includes the following steps: using piperidine-4-yl[1,1-biphenyl]-2-carbamate (compound I) as a raw material, and reacting it with compound II through a substitution reaction to obtain compound III: In compound II, X is a halogen, such as chlorine, bromine, or iodine.

2. The method according to claim 1, wherein, The substitution reaction is carried out in the presence of an acid-binding agent; Preferably, the acid-binding agent is selected from one or more of sodium carbonate, potassium carbonate, potassium bicarbonate, triethylamine, pyridine, triethylenediamine, diisopropylethylamine, and N-methylmorpholine, with triethylamine being the most preferred.

3. The method according to claim 1 or 2, wherein, The substitution reaction is carried out in the presence of a first organic solvent; Preferably, the first organic solvent is selected from one or more of chloroform, tetrahydrofuran, acetonitrile, toluene, 2-methyltetrahydrofuran, 1,4-dioxane, and ethyl acetate, with chloroform being the most preferred.

4. The method according to claims 1 to 3, wherein, The molar ratio of the acid-binding agent to compound I is (2-5):1, preferably (2-3):1; Preferably, the molar ratio of compound II to compound I is (1-5):1, more preferably (2-3):1; Preferably, the reaction temperature of the substitution reaction is 50°C to 70°C; Preferably, the reaction time of the substitution reaction is 8h-20h.

5. The method according to claims 1 to 4, wherein, The preparation method further includes the steps of extracting, washing, concentrating, recrystallizing, filtering and drying the obtained compound III; Preferably, the recrystallization is carried out in the presence of a second organic solvent; Preferably, the second organic solvent is selected from one or more of ethanol, acetonitrile, ethyl acetate, isopropanol, and 1,4-dioxane.

6. A method for preparing revanasin, the method comprising the following steps: (1) Compound III undergoes a hydrogenation reaction to yield compound IV; (2) Compound IV obtained in step (1) and compound V were subjected to a condensation reaction to obtain compound VI; (3) Compound VI obtained in step (2) is subjected to a reductive amination reaction with compound VII to obtain refennaxine. in, Compound III is prepared by the method according to any one of claims 1 to 5.

7. The method according to claim 6, wherein, In step (1), compound III is dissolved in a third organic solvent, a catalyst is added, and a hydrogenation reaction is carried out. After the reaction is completed, a fourth organic solvent is added for purification, and the mixture is cooled and stirred to obtain compound IV. Preferably, in step (1), the third organic solvent is selected from one or more of ethanol, acetic acid, methanol, tetrahydrofuran, ethyl acetate, and 2-methyltetrahydrofuran; Preferably, in step (1), the catalyst is selected from one or more of palladium on carbon, Raney nickel, platinum on carbon, and rhodium tri(triphenylphosphine)chloride; Preferably, in step (1), the amount of catalyst used is 2% to 30% of the mass of compound III; Preferably, in step (1), the reaction temperature of the hydrogenation reaction is 40°C to 65°C; Preferably, in step (1), the reaction time of the hydrogenation reaction is 2h-8h; Preferably, in step (1), the fourth organic solvent is selected from one or more of ethanol, methanol, ethyl acetate, isopropyl acetate, and acetone; Preferably, in step (1), the temperature at which the fourth organic solvent is added and then cooled and stirred is 0°C to 40°C.

8. The method according to claim 6 or 7, wherein, In step (2), the molar ratio of compound IV to compound V is 1:1.0 to 1:3.0; Preferably, in step (2), compound IV obtained in step (1) is condensed with compound V in a fifth organic solvent under condensing agent conditions. After the reaction is completed, compound VI is prepared by extraction and washing with alkaline solution, concentration, and recrystallization. Preferably, in step (2), the fifth organic solvent is selected from one or more of isopropyl acetate, ethyl acetate, dichloromethane, chloroform, acetone, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, and dimethyl sulfoxide; Preferably, in step (2), the condensing agent is selected from one or more of DCC / DMAP, CDI, HATU, HBTU, DMTMM, and EDCI / HOBt; Preferably, in step (2), the reaction temperature of the condensation reaction is 10°C to 40°C; Preferably, in step (2), the reaction time of the condensation reaction is 3h to 10h; Preferably, in step (2), the alkaline solution is selected from one or more of sodium hydroxide solution, potassium hydroxide solution, sodium bicarbonate solution, and sodium carbonate solution; Preferably, in step (2), the solvent used for recrystallization is selected from one or more of ethanol, methanol, acetonitrile, acetone, n-heptane, methyl tert-butyl ether, isopropyl ether, N,N-dimethylformamide, and dimethyl sulfoxide.

9. The method according to any one of claims 6 to 8, wherein, In step (3), compound VI obtained in step (2) and compound VII are subjected to a reducing amination reaction in the presence of a sixth organic solvent and a reducing agent to obtain refennaxine; Preferably, in step (3), the sixth organic solvent is selected from one or more of dichloromethane, chloroform, methanol, ethanol, toluene, acetone, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, and dimethyl sulfoxide; Preferably, in step (3), the molar ratio of compound VI to compound VII is 1:1.0 to 1:5.0; Preferably, in step (3), the reducing agent is selected from one or more of sodium borohydride, sodium cyanoborohydride, lithium borohydride, zinc borohydride, lithium aluminum hydride, sodium triacetoxyborohydride, sodium tri(trifluoroacetyl)borohydride, and triethylsilane; Preferably, in step (3), the molar ratio between compound VI and the reducing agent is 1:2.5 to 1:5.5; Preferably, in step (3), the reaction temperature of the reductive amination reaction is 10°C to 30°C; Preferably, in step (3), the reaction time of the reductive amination reaction is 3h to 10h; Preferably, step (3) further includes the steps of extracting, washing, concentrating, and recrystallizing the obtained revannasine; Preferably, in step (3), the solvent used for recrystallization is selected from one or more of ethanol, methanol, acetonitrile, acetone, n-heptane, methyl tert-butyl ether, isopropyl ether, N,N-dimethylformamide, and dimethyl sulfoxide, with acetone being the most preferred.

10. The method according to any one of claims 6 to 9, the method comprising the following steps: Using piperidine-4-yl[1,1-biphenyl]-2-carbamate (compound I) as a starting material, compound III was obtained by a substitution reaction with compound II; The obtained compound III was subjected to a hydrogenation reaction to obtain compound IV; The obtained compound IV and compound V were subjected to a condensation reaction to obtain compound VI; The obtained compound VI was subjected to a reductive amination reaction with compound VII to obtain refennacine; The synthesis route is as follows: Preferably, the substitution reaction is as follows: piperidine-4-yl[1,1-biphenyl]-2-carbamate (compound I) reacts with compound II and triethylamine in chloroform at 60℃~70℃ for 12~16h. After the reaction is completed, the mixture is cooled to room temperature, water is added and stirred, extracted, washed, and the organic phase is concentrated. The concentrated residue is added to ethanol for recrystallization, filtered, and dried to obtain compound III. The hydrogenation reaction is as follows: Compound III and 10% palladium on carbon are reacted in ethanol at 40℃~50℃ for 4~7h, filtered, the filtrate is concentrated, the concentrated residue is purified by ethyl acetate, cooled and stirred, filtered, and dried to obtain compound IV. The condensation reaction was as follows: Compound IV, p-formylbenzoic acid (compound V), and DMTMM were reacted in ethyl acetate at 20℃~30℃ for 3~6h. After the reaction was completed, sodium hydroxide solution was added for extraction, washing, concentration, recrystallization with acetone, filtration, and drying to obtain compound VI. The reductive amination reaction is as follows: Compound VI and 4-piperidinecarboxamide (compound VII) and sodium triacetoxyborohydride are reacted in chloroform at 10℃~30℃ for 3~6h. After the reaction is completed, the mixture is filtered, purified water is slowly added, and the mixture is extracted, separated, the organic phase is washed twice with water, dried with anhydrous sodium sulfate, filtered, the filtrate is concentrated, the concentrated residue is added to acetone for recrystallization, filtered, and dried to obtain rafenazine.

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