Method for preparing remimazolam

A technology of remimazolam and an intermediate, which is applied in the field of preparation of labor pain anesthetic drug remazolam, can solve problems such as waste, and achieve the effects of improving quality, optimizing preparation process and simple operation.

Active Publication Date: 2021-11-30

SHANGHAI ZAIQI BIO TECH

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Problems solved by technology

In this method, the racemate is first obtained through a multi-step reaction, and the undesired configuration can be obtained after resolution. Alkaline can be added to carry o...

Abstract

The invention discloses a preparation method of remimazolam, and belongs to the technical field of medical intermediates. The preparation method comprises the following steps: carrying out condensation on 2-(2-amino-5-bromo-benzoyl) pyridine (1) and BOC-glycine to obtain an intermediate (2); removing Boc protection from the intermediate (2), and performing ring closing to obtain an intermediate (3); performing sulfonylation and substitution reaction on the intermediate (3) to obtain an intermediate (4); oxidizing and cyclizing the intermediate (4) to obtain an intermediate (5); and reacting the intermediate (5) with methyl acrylate, and carrying out chiral resolution to obtain remimazolam (6). The production of an impurity II is avoided, and the quality of the product is improved; and after the resolution, the configuration is not required, alkali can be continuously added for racemization, and the resolution is performed again, so that the process reproducibility is good, and the reaction scale can be smoothly enlarged to a kilogram-level reaction scale.

Application Domain

Organic chemistry methodsBulk chemical production

Technology Topic

Chiral resolutionPyridyne +9

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Examples

Experimental program(3)

Example Embodiment

[0044] Example 1

[0045] first step:

[0046] 1- (3-dimethylaminopropyl) -3-ethyl carbon diimide (0.9 g, 4.7 mmol) was added to BOC-glycine (0.63 g, 3.61 mmol) and 2- (2-amino - 5-bromo-benzoyl) pyridine (compound (1)) (1.0 g, 3.61 mmol) / tetrahydrofuran (16 mL) solution, at room temperature for 6 hours, and EtOAc EtOAc EtOAc. The organic layer was washed with brine, dried to dry the compound 2 (1.46 g, yield 93.0%).

[0047] Step 2:

[0048]The hydrogen chloride gas is introduced into the compound 2 (1.46 g, 3.36 mmol) / methanol (15 mL) solution, and the ventilation is stopped after 20 minutes, and the solution is stirred at room temperature overnight, washed with aqueous sodium bicarbonate, and the organic layer is carried out with aqueous solution of sodium bicarbonate. (1N) Adjusting pH = 8-9, dichloromethane extraction 3 times, crystallized by methanol / water repeat crystalline compound 3 (0.90 g, yield: 84.9%).

[0049] Step 3: 7-bromo-2- (2-hydroxypropyl) amino-5- (pyridin-2-yl) -3H-benzo [E] [1,4] diazine

[0050] Compound 3 (0.90 g, 2.85 mmol) was dissolved in dichloromethane (9 mL), cooled to -5 ° C to -10 ° C, trifluoromethanesulfonic anhydride (1.61 g, 5.69 mmol) was slowly added to the reaction liquid, then continue After stirring for 1 hour, 1-amino-2-propanol (0.43 g, 5.69 mmol) / dichloromethane (2 mL) solution was slowly added to the reaction solution, stirred for 1 hour, then add water layer, dry dry, dry dry Add hydrochloric acid / dioxane (7.5 mL), dried 7-bromine-2- (2-hydroxypropyl) amino-5- (pyridin-2-yl) -3H-benzo [E] [1 4] Diazazod (intermediate 4) (0.91 g, yield: 85.8%).

[0051] Step 4: 8-bromo-1-methyl-6- (pyridin-2-yl) -4H-benzo [F] imidazole [1,2-a] [1,4] diazine (intermediate) 5) synthesis

[0052] 7-bromo-2- (2-hydroxypropyl) amino-5- (pyridin-2-yl) -3 H-benzo [E] [1,4] diazorane (intermediate 4) (0.91 g, 2.44 mmol) was dissolved in acetone (10 mL), and after the Dersassin oxidant (2.07 g, 4.88 mmol) was heated to 40 ° C to react overnight. Point plate, the basic reaction is completely completed. The reaction solution was filtered under reduced pressure. The residue was dissolved in ethyl acetate and washed three times with saturated sodium bicarbonate solution and a saturated ammonium chloride solution. -2-yl) -4H-benzo [F] imidazole [1,2-A] [1,4] Diazo hetero (intermediate 5) (0.77 g, yield: 89.5%).

[0053] Step 5: 3 - ((4S) -8-bromo-1-methyl-6- (pyridin-2-yl) -4H-benzo [f] imidazole [1,2-a] [1, 4 ] Synthesis of methyl diazeploy-4-yl) propionate

[0054] 8-bromo-1-methyl-6- (pyridin-2-yl) -4H-benzo [f] imidazole [1,2-a] [1,4] diazorasis (intermediate 5) (intermediate 5) 0.77 g, 2.18 mmol), potassium tert-butoxide (0.25 g, 2.23 mmol) and methyl acrylate (0.37 g, 4.36 mmol) were dissolved in dioxane (8 ml), and heated at 60 ° C for 5 hours, and after drying The crude product was added to 6.0 ml of ethyl acetate, saturated ammonium chloride, and D - (+) - dual methylbenzoyl tartaric acid (0.84 g, 2.18 mmol) / ethyl acetate 6.0ml solution, dripping Heat until 70 ° C for 1 hour. Cool to room temperature, white solid precipitation, drown to room temperature and stir overnight. Filtration, filtered out of ethyl acetate washing, vacuum dried to give the product-D-DTTA salt.

[0055] The above product-D-DTTA salt was added to ethyl acetate and water, and 20% hydrochloric acid was added dropwise to the organic layer without the product (less than 1.0%), the organic layer was separated. The aqueous layer was adjusted with a saturated potassium carbonate solution to adjust the pH = 9, dichloromethane extraction, combined with an organic phase, washed with water, saturated sodium chloride, dried off anhydrous sodium sulfate. Product 6 (0.41 g, yield of 42.7%, 99% EE).

Example Embodiment

[0056] Example 2

[0057] first step:

[0058] 3,5-dinitropyrobree acid (0.153 kg, 0.72 mol) was added to BOC-glycine (0.69 kg, 3.97 mol) and 2- (2-amino-5-bromo-benzoyl) pyridine (compound (1) (1 kg, 3.61 mol) / dioxane (13L) / toluene (4L) solution, refluxed for 6 hours, and EtOAc EtOAc EtOAc. The organic layer was washed with brine, dried to dry the compound 2 (1.48 kg yield 94.3%).

[0059] Step 2:

[0060] Trifluoroacetic acid (0.58 kg, 5.11 mol) was added to compound 2 (1.48 kg, 3.41 mol) dioxane (7L) solution, and the solution was stirred at room temperature overnight, washed with potassium carbonate, and the organic layer was dried. Potassium carbonate solution (1N) regulates pH = 8-9, dichloromethane extraction 3, and then carried with methanol / water recrystalline compound 3 (0.92 kg, yield 85.1%).

[0061] Step 3: 7-bromo-2- (2-hydroxypropyl) amino-5- (pyridin-2-yl) -3H-benzo [E] [1,4] diazine

[0062] Compound 3 (0.92 kg, 2.91 mol) was dissolved in acetonitrile (9L), cooled to -5 ° C to -10 ° C, trifluoromethanesulfonic anhydride (0.82 kg, 2.91 mol) was slowly added to the reaction liquid, then continued to stir 1 Hour, 1-amino-2-propanol (0.22 kg, 2.91 mol) / acetonitrile (1L) solution was slowly added to the reaction solution, stirred for 1 hour, then add moisture layers, dry the organic layer, and then add hydrochloric acid / Oxygen six ring (5.2 L), filtered dry 7-bromo-2- (2-hydroxypropyl) amino-5- (pyridine-2-yl) -3H-benzo [E] [1, 4] two Nitrogen (intermediate 4) (0.92 kg, yield: 84.4%).

[0063] Step 4: 8-bromo-1-methyl-6- (pyridin-2-yl) -4H-benzo [F] imidazole [1,2-a] [1,4] diazine (intermediate) 5) synthesis

[0064] 7-bromo-2- (2-hydroxypropyl) amino-5- (pyridin-2-yl) -3H-benzo [E] [1,4] diaza (intermediate 4) (0.92 kg, 2.46 mol) is dissolved in dichloromethane (20L), and the Days martic oxidant (4.18 kg, 9.86 mol) was added to the reflux reaction overnight. Point plate, the basic reaction is completely completed. The reaction solution was filtered under reduced pressure. The residue was dissolved in ethyl acetate and washed three times with saturated sodium bicarbonate solution and a saturated ammonium chloride solution. -2-yl) -4H-benzo [F] imidazole [1,2-A] [1,4] diaza (intermediate 5) (0.76 kg, yield: 87.4%).

[0065] Step 5: 3 - ((4S) -8-bromo-1-methyl-6- (pyridin-2-yl) -4H-benzo [f] imidazole [1,2-a] [1, 4 ] Synthesis of methyl diazeploy-4-yl) propionate

[0066] 8-bromo-1-methyl-6- (pyridin-2-yl) -4H-benzo [f] imidazole [1,2-a] [1,4] diazorasis (intermediate 5) (intermediate 5) 0.76kg, 2.20 mol) and methyl acrylate (0.22 kg, 2.58 mol) were dissolved in tetrahydrofuran (8L), heated at 60 ° C for 5 hours, and the mixture was evaporated. Ethyl acetate (6.0 L) ), Saturated ammonium chloride, dripping D - (+) - diphenyl tartaric acid (0.77 kg, 2.15 mol) / ethyl acetate (6.0 L), added to 70 ° C for 1 hour. Cool to room temperature, white solid precipitation, drown to room temperature and stir overnight. Filtered, filtered out of ethyl acetate washing, vacuum dried to give the product-DBTA salt.

[0067] The above product-D-DBTA salt was added to ethyl acetate and water, and 20% hydrochloric acid was added to the organic layer without the product (less than 1.0%), the organic layer was divided. The aqueous layer was adjusted with a saturated potassium carbonate solution to adjust the pH = 9, dichloromethane extraction, combined with an organic phase, washed with water, saturated sodium chloride, dried off anhydrous sodium sulfate. Product 6 (0.38 kg, yield is 40.2%, 99% EE).

Example Embodiment

[0068] Example 3

[0069] first step:

[0070] Boric acid tris (2,2,2-trifluoroethyl) ester (1.67 kg, 5.41 mol) was added to BOC-glycine (6.64 kg, 37.89 mol) and 2- (2-amino-5-bromo-benzoyl) Pyridine (compound (1)) (10 kg, 36.09 mol) / dioxane (140 L) / toluene (30 L) solution, refluxed for 6 hours, and EtOAc EtOAc EtOAc. The organic layer was washed with brine, dried to dryness, and the compound 2 (14.42 kg, yield was 92.0%).

[0071] Step 2:

[0072] Concentrated hydrochloric acid (4.15 L, 49.8 mol) was added to compound 2 (14.42 kg, 33.20 mol) of ethyl acetate (75L) solution, and the solution was stirred at room temperature overnight, washed with aqueous DBU, and the organic layer was dried after drying with a DBu aqueous solution ( 1N) Adjust pH = 8-9, dichloromethane extraction 3 times, crystallized with methanol / water, yield: 85.8% after drying.

[0073] Step 3: 7-bromo-2- (2-hydroxypropyl) amino-5- (pyridin-2-yl) -3H-benzo [E] [1,4] diazine

[0074] Compound 3 (9.01 kg, 28.5 mol) was dissolved in tetrahydrofuran (90L), cooled to -5 ° C to -10 ° C, trifluoromethanesulfonic anhydride (12.06 kg, 42.75 mol) was slowly added to the reaction solution, then continued to stir 1 Hour, 1-amino-2-propanol (3.21 kg, 42.75 mol) / tetrahydrofuran (16 L) solution was slowly added to the reaction solution, stirred for 1 hour, then add water layer, dry dry, dry and dry, add hydrochloric acid / Oxygen six ring (63L), filtration dry 7-bromine-2- (2-hydroxypropyl) amino-5- (pyridine-2-yl) -3H-benzo [E] [1,4] diazine Heter (Intermediate 4) (9.05 kg, yield: 85.1%).

[0075] Step 4: 8-bromo-1-methyl-6- (pyridin-2-yl) -4H-benzo [F] imidazole [1,2-a] [1,4] diazine (intermediate) 5) synthesis

[0076] 7-bromo-2- (2-hydroxypropyl) amino-5- (pyridin-2-yl) -3H-benzo [E] [1,4] diazora (intermediate 4) (9.05 kg, 24.25 mol) dissolved in acetonitrile (150 L), Diamparten oxidant (30.85 kg, 72.74 mol) was added overnight at 40 ° C. Point plate, the basic reaction is completely completed. The reaction solution was filtered under reduced pressure. The residue was dissolved in ethyl acetate and washed three times with saturated sodium bicarbonate solution and a saturated ammonium chloride solution. -2-yl) -4H-benzo [F] imidazole [1,2-A] [1,4] diaza (intermediate 5) (7.79 kg, yield: 91.0%).

[0077] Step 5: 3 - ((4S) -8-bromo-1-methyl-6- (pyridin-2-yl) -4H-benzo [f] imidazole [1,2-a] [1, 4 ] Synthesis of methyl diazeploy-4-yl) propionate

[0078]8-bromo-1-methyl-6- (pyridin-2-yl) -4H-benzo [f] imidazole [1,2-a] [1,4] diazorasis (intermediate 5) (intermediate 5) 7.79kg, 22.05 mol), tert-butoxide (2.16 kg, 22.50 mol) and methyl acrylate (2.47 kg, 28.67 mol) were dissolved in acetonitrile (80L), heated at 60 ° C for 5 hours, and the coarse was added to yield. Ethyl acetate (60L), saturated ammonium chloride, dripping D - (+) - dual methylbenzoyl ketteral acid (8.52 kg, 22.05 mol) / ethyl acetate (60L) solution, dripping The reaction was reacted at 70 ° C for 1 hour. Cool to room temperature, white solid precipitation, drown to room temperature and stir overnight. Filtration, filtered out of ethyl acetate washing, vacuum dried to give the product-D-DTTA salt.

[0079] The above product-D-DTTA salt was added to ethyl acetate and water, and 20% hydrochloric acid was added dropwise to the organic layer without the product (less than 1.0%), the organic layer was separated. The aqueous layer was adjusted with a saturated potassium carbonate solution to adjust the pH = 9, dichloromethane extraction, combined with an organic phase, washed with water, saturated sodium chloride, dried off anhydrous sodium sulfate. Product 6 (4.05 kg, yield of 41.8%, 99% EE).

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improve quality
Optimize the preparation process

Method for preparing remimazolam

A technology of remimazolam and an intermediate, which is applied in the field of preparation of labor pain anesthetic drug remazolam, can solve problems such as waste, and achieve the effects of improving quality, optimizing preparation process and simple operation.

AI-Extracted Technical Summary

Problems solved by technology

Abstract

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Examples

Example Embodiment

Example Embodiment

Example Embodiment

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Description & Claims & Application Information

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