Preparation method of remimagine intermediate

Abstract

The present invention relates to the technical field of the preparation of pharmaceutical intermediates, and provides a method for preparing a remimazolam intermediate. In the present invention, a compound having the structure shown in Formula VII and urea are subjected to reductive amination reaction, the obtained product is cyclized with a compound having the structure shown in Formula B, and then deprotected. The obtained deprotected product, N,N'-carbonyldiimidazole, an inorganic base and a solvent are mixed for reaction to obtain the remimazolam intermediate. The reaction raw materials used in the method provided by the present invention are cheap and easily available, the preparation cost is low, and it is more conducive to industrial production.

Description

Technical Field

[0001] The present invention relates to the technical field of the preparation of pharmaceutical intermediates, and in particular to a method for preparing an intermediate of rimegepant. Background Art

[0002] Rimegepant (CAS: 1374024-48-2) is an oral drug belonging to the class of tricyclic triarylamides (triptan) analogs and is used for the treatment of migraine. Different from the "triptan" drugs, Rimegepant does not constrict blood vessels but relieves migraine symptoms by blocking neurotransmitter calcium channels. The clinical trial results of Rimegepant show that it can relieve migraine symptoms within two hours and remain effective within 24 hours. The side effects of Rimegepant are relatively few, mainly including mild headache, nausea, dry mouth, etc.

[0003] Generally speaking, Rimegepant is a new type of oral drug and is an effective and convenient treatment option for migraine patients.

[0004] The molecular structure of rimegepant is shown in Formula I:

[0005]

[0006] The literature JLabelCompdRadiopharm.2022; 65, 126–139 published the following preparation method: Compound A and Compound VII undergo reductive amination reaction to form Compound VI; Compound VI undergoes ring closure in the presence of CDI (N,N′-carbonyldiimidazole) to prepare Compound V, and then the BOC protection is removed to obtain Compound IV; Compound IV reacts with CDI and then reacts with Intermediate II to obtain the final rimegepant I. The synthetic route is as follows:

[0007]

[0008] It can be found from the above route that Compound III is an intermediate for the synthesis of rimegepant, and the starting material of the above synthetic route, Compound A, is expensive, which is not conducive to cost reduction. Therefore, it is urgent to develop a method for preparing rimegepant Intermediate III with low cost. Summary of the Invention

[0009] In view of this, the present invention provides a method for preparing an intermediate of rimegepant. The preparation method provided by the present invention has low raw material cost, can significantly reduce the preparation cost of rimegepant intermediate, and is more conducive to industrial production.

[0010] In order to achieve the above invention object, the present invention provides the following technical solutions:

[0011] A preparation method of a remimagine intermediate, comprising the following steps:

[0012] (1) Mix a compound having the structure shown in Formula VII, urea, a catalyst, a reducing agent and a solvent for reductive amination reaction to obtain a compound having the structure shown in Formula C;

[0013]

[0014] (2) Mix the compound having the structure shown in Formula C, the compound having the structure shown in Formula B, a metal catalyst, an organic base and a solvent for cyclization reaction to obtain a compound having the structure shown in Formula V;

[0015]

[0016] (3) Mix the compound having the structure shown in Formula V and a hydrogen chloride ethanol solution for deprotection reaction to obtain a deprotected product; the structure of the deprotected product is as shown in Formula IV;

[0017]

[0018] (4) Mix the deprotected product, N,N′-carbonyldiimidazole, an inorganic base and a solvent for reaction to obtain the remimagine intermediate; the structure of the remimagine intermediate is as shown in Formula III;

[0019]

[0020] Preferably, the catalyst in the step (1) is trimethylchlorosilane and hexamethylphosphoric triamide; the molar amount of hexamethylphosphoric triamide is 1% - 20% of the molar amount of the compound having the structure shown in Formula VII; the molar amount of trimethylchlorosilane is 0.5 - 5 times of the molar amount of the compound having the structure shown in Formula VII.

[0021] The reducing agent in the step (1) is one or more of sodium borohydride, potassium borohydride and sodium triacetoxyborohydride; the molar amount of the reducing agent is 0.3 - 1.5 times of the molar amount of the compound having the structure shown in Formula VII.

[0022] Preferably, the molar amount of urea in the step (1) is 1 - 5 times of the molar amount of the compound having the structure shown in Formula VII.

[0023] Preferably, the temperature of the reductive amination reaction in the step (1) is -5 - 40 °C, and the time is 0.5 - 5 h;

[0024] The solvent for the reductive amination reaction in step (1) is one or more of dichloromethane, tetrahydrofuran, ethyl acetate, dimethyl sulfoxide, dimethylformamide, and acetonitrile.

[0025] Preferably, the metal catalyst in step (2) is one or more of cuprous iodide, cuprous chloride, and palladium acetate; the molar amount of the metal catalyst is 0.05% to 10% of the molar amount of the compound having the structure shown in formula C;

[0026] The organic base in step (2) is one or more of potassium tert-butoxide, sodium tert-butoxide, and sodium ethoxide; the molar amount of the organic base is 2 to 5 times the molar amount of the compound having the structure shown in formula C;

[0027] The molar amount of the compound having the structure shown in formula B in step (2) is 1 to 1.5 times the molar amount of the compound having the structure shown in formula C.

[0028] Preferably, the temperature of the cyclization reaction in step (2) is 50 to 150 °C, and the time is 3 to 30 h;

[0029] The solvent for the cyclization reaction in step (2) is one or more of dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, acetonitrile, and 1,4-dioxane.

[0030] Preferably, the temperature of the deprotection reaction in step (3) is 10 to 60 °C, and the time is 0.5 to 5 h; the mass fraction of hydrogen chloride in the hydrogen chloride ethanol solution is 5% to 40%.

[0031] Preferably, the inorganic base in step (4) is one or more of potassium carbonate, sodium carbonate, potassium bicarbonate, and sodium bicarbonate; the molar amount of the inorganic base is 1.5 to 5 times the molar amount of the compound having the structure shown in formula V;

[0032] Preferably, the molar amount of N,N′-carbonyldiimidazole in step (4) is 1 to 2 times the molar amount of the compound having the structure shown in formula V.

[0033] Preferably, the temperature of the reaction in step (4) is 20 to 80 °C, and the time is 0.5 to 5 h;

[0034] The solvent for the reaction in step (4) is one or more of acetone, acetonitrile, tetrahydrofuran, ethyl acetate, and dichloromethane.

[0035] The present invention provides a method for preparing a remimagine intermediate. In the present invention, a compound having the structure shown in Formula VII, urea, a catalyst, a reducing agent and a solvent are mixed for a reductive amination reaction to obtain a compound having the structure shown in Formula C; the compound having the structure shown in Formula C, the compound having the structure shown in Formula B, a metal catalyst, an organic base and a solvent are mixed for a cyclization reaction to obtain a compound having the structure shown in Formula V; the compound having the structure shown in Formula V and a hydrogen chloride ethanol solution are mixed for a deprotection reaction, and the obtained deprotection product, N,N'-carbonyldiimidazole, an inorganic base and a solvent are mixed for a reaction to obtain the remimagine intermediate having the structure shown in Formula III. The starting materials used in the method provided by the present invention are a compound having the structure shown in Formula VII, urea and a compound having the structure shown in Formula B. Urea is cheap and easily available. At the same time, compared with the compound A used in the prior art, the compound having the structure shown in Formula B is cheaper. Therefore, the present invention can significantly reduce the preparation cost of the remimagine intermediate having the structure shown in Formula III and is more conducive to industrial production. Detailed implementation mode

[0036] The present invention provides a method for preparing a remimagine intermediate, comprising the following steps:

[0037] (1) A compound having the structure shown in Formula VII, urea, a catalyst, a reducing agent and a solvent are mixed for a reductive amination reaction to obtain a compound having the structure shown in Formula C;

[0038]

[0039] (2) The compound having the structure shown in Formula C, the compound having the structure shown in Formula B, a metal catalyst, an organic base and a solvent are mixed for a cyclization reaction to obtain a compound having the structure shown in Formula V;

[0040]

[0041] (3) The compound having the structure shown in Formula V and a hydrogen chloride ethanol solution are mixed for a deprotection reaction to obtain a deprotection product; the structure of the deprotection product is shown in Formula IV;

[0042]

[0043] (4) The deprotection product, N,N'-carbonyldiimidazole, an inorganic base and a solvent are mixed for a reaction to obtain the remimagine intermediate; the structure of the remimagine intermediate is shown in Formula III;

[0044]

[0045] The synthetic route of the present invention is as follows:

[0046]

[0047] The method of the present invention will be described in detail below in combination with the synthetic route.

[0048] In the present invention, a compound having the structure shown in Formula VII, a catalyst, a reducing agent, and a solvent are mixed to carry out a reductive amination reaction to obtain a compound having the structure shown in Formula C. In the present invention, the catalyst in step (1) is preferably trimethylchlorosilane and hexamethylphosphoric triamide; the molar amount of the hexamethylphosphoric triamide is preferably 1% to 20% of the molar amount of the compound having the structure shown in Formula VII, more preferably 2% to 10%; the molar amount of the trimethylchlorosilane is preferably 0.5 to 5 times the molar amount of the compound having the structure shown in Formula VII, more preferably 1 to 3 times.

[0049] In the present invention, the reducing agent is preferably one or more of sodium borohydride, potassium borohydride, and sodium triacetoxyborohydride; the molar amount of the reducing agent is preferably 0.3 to 1.5 times the molar amount of the compound having the structure shown in Formula VII, more preferably 0.5 to 1.2 times.

[0050] In the present invention, the molar amount of the urea is preferably 1 to 5 times the molar amount of the compound having the structure shown in Formula VII, more preferably 1 to 2.5 times.

[0051] In the present invention, the solvent for the reductive amination reaction is preferably one or more of dichloromethane, tetrahydrofuran, ethyl acetate, dimethyl sulfoxide, dimethylformamide, and acetonitrile, more preferably dichloromethane; the present invention has no special requirements for the amount of the solvent, as long as the reductive amination reaction can proceed smoothly.

[0052] In the present invention, the temperature of the reductive amination reaction is preferably -5 to 40 °C, more preferably 0 to 30 °C, and the time of the reductive amination reaction is preferably 0.5 to 5 h, more preferably 1 to 2 h.

[0053] In a specific embodiment of the present invention, it is preferred to first mix the compound having the structure shown in Formula VII, urea, a solvent, and hexamethylphosphoric triamide, and adjust the temperature of the mixture to 0 to 5 °C, then add trimethylchlorosilane under stirring conditions, and react at 0 to 5 °C for 30 min after the addition is completed, and then slowly add the reducing agent. After the addition of the reducing agent is completed, the reductive amination reaction is carried out at room temperature; the addition time of the reducing agent is preferably 2 h.

[0054] After the reductive amination reaction is completed, the present invention preferably separates the product liquid to obtain an aqueous phase and an organic phase, extracts the aqueous phase with dichloromethane to obtain an extracted organic phase, combines the extracted organic phase and the organic phase obtained by liquid separation, and then successively performs water washing, drying with anhydrous sodium sulfate, filtration, and rotary evaporation to obtain a crude product; the crude product is stirred and mixed with ethyl acetate and heptane and then filtered, and the obtained solid product is dried to obtain a compound having the structure shown in Formula C; the volume ratio of ethyl acetate to heptane is preferably 1:4; the temperature of the stirring and mixing is preferably room temperature, and the time is preferably 2 h.

[0055] After obtaining the compound having the structure shown in Formula C, the present invention mixes the compound having the structure shown in Formula C, the compound having the structure shown in Formula B, a metal catalyst, an organic base, and a solvent to carry out a cyclization reaction to obtain a compound having the structure shown in Formula V. In the present invention, the metal catalyst is preferably one or more of copper iodide, copper chloride, and palladium acetate, more preferably copper iodide; the molar amount of the metal catalyst is preferably 0.05% to 10% of the molar amount of the compound having the structure shown in Formula C, more preferably 1% to 6%.

[0056] In the present invention, the organic base is preferably one or more of potassium tert-butoxide, sodium tert-butoxide, and sodium ethoxide, more preferably potassium tert-butoxide; the molar amount of the organic base is preferably 2 to 5 times the molar amount of the compound having the structure shown in Formula C, more preferably 2.5 to 3.5 times.

[0057] In the present invention, the molar amount of the compound having the structure shown in Formula B is preferably 1 to 1.5 times the molar amount of the compound having the structure shown in Formula C, more preferably 1 to 1.2 times.

[0058] In the present invention, the solvent for the cyclization reaction is preferably one or more of dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, acetonitrile, and 1,4-dioxane, more preferably dimethyl sulfoxide; the present invention has no special requirements for the amount of the solvent, as long as the cyclization reaction can proceed smoothly.

[0059] In the present invention, the temperature of the cyclization reaction is preferably 50 to 150 °C, more preferably 60 to 120 °C. The time of the cyclization reaction is preferably 3 to 30 h. The cyclization reaction is preferably carried out under a protective atmosphere, and the protective atmosphere is preferably nitrogen. In a specific embodiment of the present invention, the cyclization reaction preferably includes a first stage and a second stage carried out in sequence. The temperature of the first stage is preferably 50 to 90 °C, more preferably 70 to 80 °C, and the time is preferably 3 to 10 h, more preferably 5 to 6 h. The temperature of the second stage is preferably 90 to 120 °C, more preferably 100 to 110 °C, and the time is preferably 5 to 20 h, more preferably 8 to 10 h. In the present invention, the cyclization reaction is carried out in two stages. In the first stage, an intermolecular substitution reaction occurs, and in the second stage, an intramolecular coupling reaction occurs. The selectivity of the intermolecular substitution reaction can be improved through the reactions of the two stages.

[0060] In a specific embodiment of the present invention, preferably, a compound having the structure shown in Formula C, a compound having the structure shown in Formula B, a metal catalyst, an organic base, and a solvent are mixed, and the temperature is raised to the reaction temperature of the first stage under nitrogen protection for reaction. After the reaction in the first stage is completed, the temperature is further raised to the reaction temperature of the second stage for reaction.

[0061] After the cyclization reaction is completed, in the present invention, preferably, the obtained product liquid is cooled to room temperature and then filtered. The obtained filtrate is mixed with water, and then the pH value of the mixed solution is adjusted to 6 to 7 with hydrochloric acid to precipitate the product. After stirring for 30 min, it is filtered again. The obtained solid product is washed with water and then dried to obtain a compound having the structure shown in Formula V.

[0062] After obtaining the compound having the structure shown in Formula V, in the present invention, the compound having the structure shown in Formula V and a hydrogen chloride ethanol solution are mixed for a deprotection reaction to obtain a deprotected product, and the structure of the deprotected product is as shown in Formula IV. In the present invention, the mass fraction of hydrogen chloride in the hydrogen chloride ethanol solution is preferably 5% to 40%, more preferably 30%. The dosage ratio of the compound having the structure shown in Formula V to the hydrogen chloride ethanol solution is preferably 1 mmol:1 mL. The temperature of the deprotection reaction is preferably 10 to 60 °C, more preferably 20 to 25 °C, and the time is preferably 0.5 to 5 h, more preferably 2 h. After the deprotection reaction is completed, preferably, the solvent in the product liquid is rotary evaporated, the remaining product is mixed with acetone and then rotary evaporated again to obtain the deprotected product.

[0063] After obtaining the deprotected product, the present invention mixes the deprotected product, N,N′-carbonyldiimidazole, an inorganic base, and a solvent for reaction to obtain the Remimazolam intermediate; the structure of the Remimazolam intermediate is shown in Formula III. In the present invention, the inorganic base is preferably one or more of potassium carbonate, sodium carbonate, potassium bicarbonate, and sodium bicarbonate, more preferably potassium carbonate; the molar amount of the inorganic base is preferably 1.5 to 5 times, more preferably 2 to 3 times, the molar amount of the compound having the structure shown in Formula V.

[0064] In the present invention, the molar amount of the N,N′-carbonyldiimidazole (CDI) is preferably 1 to 2 times, more preferably 1.2 to 1.6 times, the molar amount of the compound having the structure shown in Formula V.

[0065] In the present invention, the solvent for the reaction in step (4) is preferably one or more of acetone, acetonitrile, tetrahydrofuran, ethyl acetate, and dichloromethane, more preferably acetone; the present invention has no special requirements for the amount of the solvent, as long as the reaction can proceed smoothly.

[0066] In the present invention, the reaction temperature in step (4) is preferably 20 to 80°C, more preferably 50 to 60°C, and the time is preferably 0.5 to 5 h, more preferably 2 h.

[0067] In a specific embodiment of the present invention, it is preferred to mix the deprotected product, the solvent, CDI, and the inorganic base, and then raise the temperature to the reaction temperature for reaction.

[0068] After the reaction is completed, the present invention preferably removes the solvent in the obtained product liquid by rotary evaporation, then mixes the remaining product with water and extracts with dichloromethane. The obtained organic phase is dried with anhydrous sodium sulfate and then filtered, and the filtrate is rotary evaporated to obtain the compound having the structure shown in Formula III.

[0069] Next, the technical solutions in the present invention will be clearly and completely described in conjunction with the embodiments in the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments in the present invention, all other embodiments obtained by those of ordinary skill in the art without making creative efforts belong to the scope of protection of the present invention.

[0070] In the following examples, the compounds having the structures shown in Formula VII, Formula C, Formula B, Formula V, and Formula III are respectively denoted as Compound VII, Compound C, Compound B, Compound V, and Compound III.

[0071] Example 1 Preparation of Compound C

[0072]

[0073] Add 20.0 g of Compound VII, 9.0 g of urea, 200 mL of dichloromethane, and 0.90 g of hexamethylphosphoric triamide into a flask. Cool the mixture to 0 - 5 °C in an ice - water bath, and gradually add 16.3 g of trimethylchlorosilane with stirring. After the addition, continue stirring at 0 - 5 °C for 30 min, then slowly add 3.8 g of sodium borohydride in portions over about 2 h. Remove the ice - water bath and stir the reaction at room temperature for 1 h. Add 200 mL of water, stir for 30 min, separate the layers, extract the aqueous phase with 100 mL of dichloromethane again, combine the organic phases, wash with 50 mL of water, dry over anhydrous sodium sulfate, filter, and rotary - evaporate to dryness. Add 20 mL of ethyl acetate and 80 mL of heptane to the obtained crude product, stir at room temperature for 2 h, filter, and dry to obtain 22.4 g of white solid Compound C with a yield of 92%.

[0074] The 1H - NMR data of the product are as follows: 1 1H - NMR(400M, CDCl3): 8.95(1H, brs), 4.25(2H, brs), 3.26(1H, brs), 2.75(2H, brs), 2.08(4H, brs), 1.78(2H, brs), 1.49(9H, s).

[0075] Preparation of Compound C in Example 2

[0076] Add 20.0 g of Compound VII, 7.2 g of urea, 200 mL of tetrahydrofuran, and 0.54 g of hexamethylphosphoric triamide into a flask. Cool the mixture to 0 - 5 °C in an ice - water bath, and gradually add 21.7 g of trimethylchlorosilane with stirring. After the addition, continue stirring at 0 - 5 °C for 30 min, then slowly add 27.6 g of sodium triacetoxyborohydride in portions over about 2 h. Remove the ice - water bath and stir the reaction at room temperature for 2 h. Rotary - evaporate the solvent, add 200 mL of water, stir for 30 min, filter, wash with 50 mL of water, and dry. Add 20 mL of ethyl acetate and 80 mL of heptane to the obtained crude product, stir at room temperature for 2 h, filter, and dry to obtain 22.7 g of white solid Compound C with a yield of 93%.

[0077] Preparation of Compound V in Example 3

[0078]

[0079] Add 4.87 g of Compound C, 3.26 g of Compound B, 0.12 g of copper(I) iodide, 6.73 g of potassium tert - butoxide, and 50 mL of DMSO into a flask. Under nitrogen protection, heat the mixture to 80 °C and react for 6 h, then heat to 110 °C and react for 10 h. Cool to room temperature, filter, pour the filtrate into 200 mL of water, adjust the pH to 6 - 7 with hydrochloric acid, stir for 30 min. Filter again, wash with 20 mL of water, and dry to obtain 5.67 g of white solid Compound V with a yield of 89%.

[0080] The 1H NMR data of the product are as follows: 1 1H-NMR(400M, DMSO): 11.59(1H, brs), 7.90(1H, d), 7.53(1H, d), 6.96(1H, m), 4.37(1H, m), 4.12(2H, brs), 2.88(2H, brs), 2.15(2H, m), 1.75(2H, brs), 1.44(9H, s).

[0081] Preparation of Compound V in Example 4

[0082] Add 4.87 g of Compound C, 3.56 g of Compound B, 45 mg of palladium acetate, 7.40 g of potassium tert-butoxide and 50 mL of DMF into a flask. Under nitrogen protection, heat the mixture to 70 °C and react for 5 h, then heat to 100 °C and react for 8 h. Cool to room temperature, filter, pour the filtrate into 200 mL of water, adjust the pH to 6 - 7 with hydrochloric acid, stir for 30 min. Filter again, wash with 20 mL of water, and dry to obtain 5.92 g of white solid Compound V with a yield of 93%.

[0083] Preparation of Compound III in Example 5

[0084]

[0085] Add 3.18 g of Compound V and 10 mL of hydrogen chloride ethanol solution (30% mass fraction) into a flask, stir at room temperature for 2 h, spin off the solvent, then add 10 mL of acetone and spin dry again. Add 30 mL of acetone, 2.43 g of CDI and 2.90 g of potassium carbonate powder to the obtained product, heat to 50 °C and react for 2 h, spin off the solvent, add 30 mL of cold water, extract with dichloromethane (3 times, 30 mL each time), dry over anhydrous sodium sulfate, filter, and spin dry to obtain 3.0 g of white solid Compound III with a yield of 96%.

[0086] The 1H NMR data of the product are as follows: 1 1H-NMR(400M, DMSO): 11.62(1H, brs), 8.11(1H, s), 7.93(1H, dd), 7.76(1H, d), 7.56(1H, t), 6.97 - 7.12(2H, m), 4.54(1H, t), 4.06(2H, d), 3.25(2H, t), 2.26 - 2.43(2H, m), 1.83(2H, d).

[0087] Preparation of Compound III in Example 6

[0088] Add 3.18 g of Compound V and 10 mL of hydrogen chloride ethanol solution (30% by mass fraction) to a flask, stir and react at room temperature for 2 h, rotary evaporate the solvent, then add 10 mL of acetonitrile and rotary evaporate to dryness again; add 30 mL of acetonitrile, 2.11 g of CDI and 3.18 g of sodium carbonate powder to the obtained product, heat up to 60 °C and react for 2 h, rotary evaporate the solvent, add 30 mL of cold water, extract with dichloromethane (3 times, 30 mL each time), dry over anhydrous sodium sulfate, filter, rotary evaporate to dryness, and obtain 2.94 g of white solid Compound III with a yield of 94%.

[0089] Example 7 Preparation of Remimazolam (Compound I)

[0090]

[0091] Add 2.90 g of Compound II, 50 mL of tetrahydrofuran and 2.58 g of potassium tert-butoxide to a flask, stir at room temperature for 10 min; add 3.44 g of Compound III, stir and react at room temperature for 1 h; rotary evaporate the solvent, add 50 mL of water, adjust the pH to 12 with liquid alkali, stir at room temperature for 2 h, then adjust the pH to neutral with hydrochloric acid, stir at room temperature for 1 h, filter, wash with 20 mL of water, and dry; add 20 mL of ethyl acetate to the obtained crude product, heat to 50 °C and stir for 10 min, gradually add 60 mL of heptane while maintaining 50 °C, remove the heating after adding, stir and react at room temperature for 3 h, filter, and dry to obtain 4.81 g of yellow solid Compound I with a yield of 90%.

[0092] The 1H NMR data of the product are as follows: 1 1H-NMR (400 M, DMSO): 11.61 (1H, brs), 8.51 (1H, brs), 8.08 (1H, d), 7.94 (1H, d), 7.55 (1H, brs), 7.17–7.47 (4H, m), 7.05 (1H, brs), 6.02 (1H, dd), 4.31–4.58 (3H, m), 4.12 (1H, brs), 3.10 (1H, brs), 2.98 (1H, brs), 2.79–2.92 (1H, m), 2.04–2.33 (4H, m), 1.61–1.83 (6H, m).

[0093] The above are only the preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and refinements can be made, and these improvements and refinements should also be regarded as the protection scope of the present invention.

Claims

1. A preparation method of remimagine intermediate, characterized in that, It includes the following steps: (1) Mix a compound with the structure shown in Formula VII, urea, a catalyst, a reducing agent, and a solvent for reductive amination reaction to obtain a compound with the structure shown in Formula C; the catalyst is trimethylchlorosilane and hexamethylphosphoric triamide; the reducing agent is one or more of sodium borohydride, potassium borohydride, and sodium triacetoxyborohydride; (2) Mix the compound with the structure shown in Formula C, the compound with the structure shown in Formula B, a metal catalyst, an organic base, and a solvent for cyclization reaction to obtain a compound with the structure shown in Formula V; the metal catalyst is one or more of cuprous iodide, cuprous chloride, and palladium acetate; the organic base is one or more of potassium tert-butoxide, sodium tert-butoxide, and sodium ethoxide; (3) Mix the compound with the structure shown in Formula V and an ethanolic hydrogen chloride solution for deprotection reaction to obtain a deprotected product; the structure of the deprotected product is as shown in Formula IV; (4) Mix the deprotected product, N,N′-carbonyldiimidazole, an inorganic base, and a solvent for reaction to obtain the Remimazolam intermediate; the structure of the Remimazolam intermediate is as shown in Formula III; 2. The preparation method according to claim 1, wherein The molar amount of the hexamethylphosphoric triamide is 1% - 20% of the molar amount of the compound with the structure shown in Formula VII; the molar amount of the trimethylchlorosilane is 0.5 - 5 times the molar amount of the compound with the structure shown in Formula VII; The molar amount of the reducing agent is 0.3 - 1.5 times the molar amount of the compound with the structure shown in Formula VII.

3. The preparation method according to claim 1, characterized in that In step (1), the molar amount of urea is 1 - 5 times the molar amount of the compound with the structure shown in Formula VII.

4. The preparation method according to claim 1, wherein, In step (1), the temperature of the reductive amination reaction is -5 - 40°C, and the time is 0.5 - 5 h; In step (1), the solvent for the reductive amination reaction is one or more of dichloromethane, tetrahydrofuran, ethyl acetate, dimethyl sulfoxide, dimethylformamide, and acetonitrile.

5. The preparation method according to claim 1, characterized in that, The molar amount of the metal catalyst is 0.05% - 10% of the molar amount of the compound with the structure shown in Formula C; The molar amount of the organic base is 2 - 5 times the molar amount of the compound with the structure shown in Formula C; In step (2), the molar amount of the compound with the structure shown in Formula B is 1 - 1.5 times the molar amount of the compound with the structure shown in Formula C.

6. The preparation method according to claim 1, characterized in that, In step (2), the temperature of the cyclization reaction is 50 - 150°C, and the time is 3 - 30 h; In step (2), the solvent for the cyclization reaction is one or more of dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, acetonitrile, and 1,4-dioxane.

7. The preparation method according to claim 1, characterized in that, In step (3), the temperature of the deprotection reaction is 10 - 60°C, and the time is 0.5 - 5 h; the mass fraction of hydrogen chloride in the ethanolic hydrogen chloride solution is 5% - 40%.

8. The preparation method according to claim 1, characterized in that The inorganic base in step (4) is one or more of potassium carbonate, sodium carbonate, potassium bicarbonate, and sodium bicarbonate; the molar amount of the inorganic base is 1.5 - 5 times the molar amount of the compound with the structure shown in Formula V.

9. The preparation method according to claim 1, wherein In the step (4), the molar amount of N,N'-carbonyldiimidazole is 1 to 2 times the molar amount of the compound having the structure shown in Formula V.

10. The preparation method according to claim 1, wherein, In the step (4), the reaction temperature is 20 to 80 °C and the time is 0.5 to 5 h; In the step (4), the reaction solvent is one or more of acetone, acetonitrile, tetrahydrofuran, ethyl acetate, and dichloromethane.

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