Method for preparing remazolam key intermediate

Abstract

The invention discloses a preparation method of a remazolam key intermediate (3S)-7-bromo-2,3-dihydro-2-oxo-5-(2-pyridyl)-1H-1,4-benzodiazepine-3-methyl propionate, and belongs to the technical field of medical intermediates. Herein, 2-(2-amino-5-bromo-benzoyl)pyridine A and N-Tr-glutamic acid-5-methyl ester are adopted as raw materials, a condensation reaction is performed under the action of a boron-containing reagent to obtain a compound B, then deprotection is performed to obtain a compound C, and finally ring closing is performed under the alkaline low-temperature condition to obtain a compound D. The method is good in process reproducibility, simple, convenient and stable to operate, easy to separate products in each step, high in yield, environment-friendly and suitable for industrial large-scale production.

Description

technical field

[0001] The invention belongs to the technical field of medicine, and in particular relates to a preparation method of a key intermediate of remimazolam, an anesthetic for labor pains. Background technique

[0002] Remimazolam is an ultra-short-acting intravenous benzodiazepine sedative / anesthetic that acts on GABA-α receptors. In humans, Remimazolam is rapidly metabolized by tissue esterases into inactive metabolites and is not metabolized by cytochrome-dependent hepatic pathways. It has the characteristics of fast effect, short duration, fast recovery and good tolerance. Remimazolam is used for anesthesia induction, maintenance of anesthesia and day surgery anesthesia. Compared with other products, it has certain advantages when applied to patients with cardiovascular disease, respiratory system disease, liver disease and elderly patients.

[0003] Remimazolam besylate was officially approved for marketing in July 2020. It is used in the fields of painless...

Examples

Embodiment 1

[0032] first step:

[0033] 2-(2-Amino-5-bromo-benzoyl)pyridine (38.6g, 139mmol) and N-Cbz glutamate-5-methyl ester (45.2g, 153mmol) were added into dichloromethane ( 200 mL), then the solution was cooled to -10°C. A solution of N,N'-dicyclohexylcarbodiimide (32.2g, 156mmol) in dichloromethane (65mL) was slowly added to the above solution at -10°C, and the reaction was stirred at -10°C for 48 hours, and the reaction solution Heat up to 15°C and filter. The filtrate was distilled under reduced pressure below 25°C, then 250mL of methyl tert-butyl ether was added, the solution was heated to 50°C and then slowly cooled to 25°C, filtered and dried at 50°C to obtain a light yellow solid (72.3g, yield: 93.6% ).

[0034] Step two:

[0035] Add intermediate B (35g, 63mmol) into glacial acetic acid (70mL), slowly add 33% hydrogen bromide / glacial acetic acid solution (45.7mL, 253mmol) into the above reaction solution at 10-12°C, and raise the temperature after adding to 20°C and sti...

Embodiment 2

[0037] first step:

[0038] N-Tr-glutamate-5-methyl ester (0.58g, 3.61mmol), 2-(2-amino-5-bromo-benzoyl)pyridine A (1.0g, 3.61mmol) and dioxane Mix 8mL / cyclohexane 25mL and stir evenly. Then add B(OCH 2 CF 3 ) 3 (0.22g, 0.72mmol) was heated and refluxed for water separation for 8 hours, and TLC detected that the reaction was complete. Concentrate under reduced pressure, add ethyl acetate and water to extract the reaction. Washed with saturated brine, and the organic layer was rotary evaporated to obtain a crude product, which was recrystallized from methanol / water to obtain 1.46 g of intermediate B with a yield of 93.0%.

[0039] Step two:

[0040] Hydrogen chloride gas was passed into a solution of B (1.46g, 2.2mmol) in tetrahydrofuran (15ml) for 15 minutes, TLC showed that after deprotection was completed, the temperature was lowered to -5°C, and then morpholine (0.96g, 11mmol) was added dropwise. After the addition, keep the reaction at low temperature for 2 hours. ...

Embodiment 3

[0042] first step:

[0043]Add N-Tr-glutamic acid-5-methyl ester E (1.2kg, 2.99mol) and 2-(2-amino-5-bromo-benzoyl)pyridine A (0.69kg, 2.49mol) into tetrahydrofuran 5L / Toluene 11L solvent, stir well. Then B(C6F5)3 (61.4g, 0.12mol) was added, and the temperature was raised to reflux for water separation and reaction for 6 hours, and TLC detected that the reaction was complete. Concentrate under reduced pressure, add ethyl acetate and water to extract the reaction. The organic layer was washed with brine, dried and spin-dried to obtain a crude product, which was recrystallized from methanol / water to obtain 1.5 kg of Intermediate B with a yield of 91.5%.

[0044] Step two:

[0045] Add intermediate B (1.5kg, 2.26mol) and acetic acid (0.2kg, 3.39mol) to dioxane (8L). After TLC shows that the protection is complete, cool down to -10°C, and then start adding triethylamine dropwise (1.14kg, 11.3mmol), keep the reaction at low temperature for 2 hours after the dropwise addition. ...

technical field

[0001] The invention belongs to the technical field of medicine, and in particular relates to a preparation method of a key intermediate of remimazolam, an anesthetic for labor pains. Background technique

[0002] Remimazolam is an ultra-short-acting intravenous benzodiazepine sedative / anesthetic that acts on GABA-α receptors. In humans, Remimazolam is rapidly metabolized by tissue esterases into inactive metabolites and is not metabolized by cytochrome-dependent hepatic pathways. It has the characteristics of fast effect, short duration, fast recovery and good tolerance. Remimazolam is used for anesthesia induction, maintenance of anesthesia and day surgery anesthesia. Compared with other products, it has certain advantages when applied to patients with cardiovascular disease, respiratory system disease, liver disease and elderly patients.

[0003] Remimazolam besylate was officially approved for marketing in July 2020. It is used in the fields of painless...

Examples

Embodiment 1

[0032] first step:

[0033] 2-(2-Amino-5-bromo-benzoyl)pyridine (38.6g, 139mmol) and N-Cbz glutamate-5-methyl ester (45.2g, 153mmol) were added into dichloromethane ( 200 mL), then the solution was cooled to -10°C. A solution of N,N'-dicyclohexylcarbodiimide (32.2g, 156mmol) in dichloromethane (65mL) was slowly added to the above solution at -10°C, and the reaction was stirred at -10°C for 48 hours, and the reaction solution Heat up to 15°C and filter. The filtrate was distilled under reduced pressure below 25°C, then 250mL of methyl tert-butyl ether was added, the solution was heated to 50°C and then slowly cooled to 25°C, filtered and dried at 50°C to obtain a light yellow solid (72.3g, yield: 93.6% ).

[0034] Step two:

[0035] Add intermediate B (35g, 63mmol) into glacial acetic acid (70mL), slowly add 33% hydrogen bromide / glacial acetic acid solution (45.7mL, 253mmol) into the above reaction solution at 10-12°C, and raise the temperature after adding to 20°C and sti...

Embodiment 2

[0037] first step:

[0038] N-Tr-glutamate-5-methyl ester (0.58g, 3.61mmol), 2-(2-amino-5-bromo-benzoyl)pyridine A (1.0g, 3.61mmol) and dioxane Mix 8mL / cyclohexane 25mL and stir evenly. Then add B(OCH 2 CF 3 ) 3 (0.22g, 0.72mmol) was heated and refluxed for water separation for 8 hours, and TLC detected that the reaction was complete. Concentrate under reduced pressure, add ethyl acetate and water to extract the reaction. Washed with saturated brine, and the organic layer was rotary evaporated to obtain a crude product, which was recrystallized from methanol / water to obtain 1.46 g of intermediate B with a yield of 93.0%.

[0039] Step two:

[0040] Hydrogen chloride gas was passed into a solution of B (1.46g, 2.2mmol) in tetrahydrofuran (15ml) for 15 minutes, TLC showed that after deprotection was completed, the temperature was lowered to -5°C, and then morpholine (0.96g, 11mmol) was added dropwise. After the addition, keep the reaction at low temperature for 2 hours. ...

Embodiment 3

[0042] first step:

[0043]Add N-Tr-glutamic acid-5-methyl ester E (1.2kg, 2.99mol) and 2-(2-amino-5-bromo-benzoyl)pyridine A (0.69kg, 2.49mol) into tetrahydrofuran 5L / Toluene 11L solvent, stir well. Then B(C6F5)3 (61.4g, 0.12mol) was added, and the temperature was raised to reflux for water separation and reaction for 6 hours, and TLC detected that the reaction was complete. Concentrate under reduced pressure, add ethyl acetate and water to extract the reaction. The organic layer was washed with brine, dried and spin-dried to obtain a crude product, which was recrystallized from methanol / water to obtain 1.5 kg of Intermediate B with a yield of 91.5%.

[0044] Step two:

[0045] Add intermediate B (1.5kg, 2.26mol) and acetic acid (0.2kg, 3.39mol) to dioxane (8L). After TLC shows that the protection is complete, cool down to -10°C, and then start adding triethylamine dropwise (1.14kg, 11.3mmol), keep the reaction at low temperature for 2 hours after the dropwise addition. ...

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