Method for preparing dexmedetomidine

Abstract

The invention provides a method for preparing dexmedetomidine, and particularly provides a method for preparing medetomidine midbody 1-(2,3-dimethyl phenyl)-1-(1-trityl-1H-imidazole-4-base) ethyl alcohol. The compound medetomidine midbody as shown in formula I is synthesized through Grignard reaction. The invention further provides a method for preparing dexmedetomidine hydrochloride. The technology has the advantages that the number of steps is small, yield is high, operation is easy, and product purity is high and is quite suitable for industrial production.

Description

technical field

[0001] The invention relates to a preparation method of dexmedetomidine hydrochloride and an intermediate thereof. Background technique

[0002] Dexmedetomidine Hydrochloride Injection is an α2-adrenoceptor agonist jointly developed by Orion Pharma (Finland) and Abott (USA). Listed in Japan. This product is the dextroisomer of the α2-adrenoceptor agonist medetomidine. Compared with medetomidine, this product is more selective for central α2-adrenoceptor agonism and has a shorter half-life , the dosage is very small, it is clinically suitable for the sedation of intubation and ventilator patients during intensive care treatment, and the marketed dosage form of this product is 2mL injection.

[0003] Medetomidine, its chemical name is 5-[1-(2,3-dimethylphenyl) ethyl]-1H-imidazole, and dexmedetomidine is its dextroisomer, which is derived from medetomidine Split to get, the structure is as follows:

[0004]

[0005] US4544664 discloses the preparation of ...

Examples

Embodiment 1

[0046] Example 1: Preparation of 1-(2,3-dimethylphenyl)-1-(1-trityl-1H-imidazol-4-yl)ethanol

[0047]

[0048] Step 1: Preparation of 1-trityl-1-H imidazole Grignard reagent

[0049] Under the protection of nitrogen, in a 1L reaction flask, add 4-iodo-1-trityl-1-H imidazole (144g, 330mmol) dissolved in 720ml of tetrahydrofuran, drop ethylmagnesium bromide (330mmol, 1M tetrahydrofuran solution), stirred at room temperature for 30 min, and set aside.

[0050] Step 2: preparation of formula I compound

[0051] Nitrogen protection, add anhydrous ZnCl in Schlenk reactor 2 (4.1g, 30mmol), LiCl (14g, 330mmol), tetrabutylammonium bromide (1M ether solution, 60mL, 60mmol), stirred at room temperature for 15 minutes. Add the tetrahydrofuran solution of (1-trityl-1H-imidazol-4-yl)magnesium bromide prepared above, stir at room temperature for 30 min, concentrate part of the solvent under reduced pressure to about 330 ml, and cool the mixture to 0 °C. Add a solution of 2,3-dimethyla...

Embodiment 13

[0068] Embodiment 13: the preparation of medetomidine

[0069]

[0070] In a 3L reaction flask, put 4-[(2,3-dimethylphenyl)-1-hydroxyethyl]-1-(triphenylmethyl)imidazole 46g (100mmol), triethylsilane 59.3 g, 1400ml of dichloromethane, cooled to -10°C, 80ml of trifluoroacetic acid was added dropwise under stirring, the dropwise was completed in about 1 hour, and the reaction was continued for 4 hours, then slowly raised to room temperature, and reacted overnight. Wash three times with 300ml of saturated sodium bicarbonate solution, once with 300ml of water, dry over anhydrous sodium sulfate, concentrate to dryness, add 650ml of ethyl acetate, extract with 2N hydrochloric acid (75ml×4), combine the extracts, add 10% Pd / C 0.7 g, normal pressure through H 2 Reduce overnight, filter with celite, neutralize with 20% sodium hydroxide solution, extract with ethyl acetate (300ml×2), combine the organic layers, wash with brine (150ml), dry over anhydrous sodium sulfate, and concentr...

Embodiment 14

[0072] Example 14: Preparation of (S)-dexmedetomidine-L-(+)-tartrate

[0073] L-(+)-tartaric acid (9 g, 60 mmol) was added to a solution of medetomidine (12 g, 60 mmol) in ethanol (250 ml). The suspension was heated to reflux until completely dissolved, then stirred overnight at room temperature, and filtered to obtain a white solid (9 g). The resulting solid was dissolved in isopropanol (200ml) under reflux, stirred overnight at room temperature, and filtered to obtain (13.5g). The obtained solid was refined again by the same method to obtain 8.1 g of solid with a purity of 99.9% and a yield of 77.1%.

technical field

[0001] The invention relates to a preparation method of dexmedetomidine hydrochloride and an intermediate thereof. Background technique

[0002] Dexmedetomidine Hydrochloride Injection is an α2-adrenoceptor agonist jointly developed by Orion Pharma (Finland) and Abott (USA). Listed in Japan. This product is the dextroisomer of the α2-adrenoceptor agonist medetomidine. Compared with medetomidine, this product is more selective for central α2-adrenoceptor agonism and has a shorter half-life , the dosage is very small, it is clinically suitable for the sedation of intubation and ventilator patients during intensive care treatment, and the marketed dosage form of this product is 2mL injection.

[0003] Medetomidine, its chemical name is 5-[1-(2,3-dimethylphenyl) ethyl]-1H-imidazole, and dexmedetomidine is its dextroisomer, which is derived from medetomidine Split to get, the structure is as follows:

[0004]

[0005] US4544664 discloses the preparation of ...

Examples

Embodiment 1

[0046] Example 1: Preparation of 1-(2,3-dimethylphenyl)-1-(1-trityl-1H-imidazol-4-yl)ethanol

[0047]

[0048] Step 1: Preparation of 1-trityl-1-H imidazole Grignard reagent

[0049] Under the protection of nitrogen, in a 1L reaction flask, add 4-iodo-1-trityl-1-H imidazole (144g, 330mmol) dissolved in 720ml of tetrahydrofuran, drop ethylmagnesium bromide (330mmol, 1M tetrahydrofuran solution), stirred at room temperature for 30 min, and set aside.

[0050] Step 2: preparation of formula I compound

[0051] Nitrogen protection, add anhydrous ZnCl in Schlenk reactor 2 (4.1g, 30mmol), LiCl (14g, 330mmol), tetrabutylammonium bromide (1M ether solution, 60mL, 60mmol), stirred at room temperature for 15 minutes. Add the tetrahydrofuran solution of (1-trityl-1H-imidazol-4-yl)magnesium bromide prepared above, stir at room temperature for 30 min, concentrate part of the solvent under reduced pressure to about 330 ml, and cool the mixture to 0 °C. Add a solution of 2,3-dimethyla...

Embodiment 13

[0068] Embodiment 13: the preparation of medetomidine

[0069]

[0070] In a 3L reaction flask, put 4-[(2,3-dimethylphenyl)-1-hydroxyethyl]-1-(triphenylmethyl)imidazole 46g (100mmol), triethylsilane 59.3 g, 1400ml of dichloromethane, cooled to -10°C, 80ml of trifluoroacetic acid was added dropwise under stirring, the dropwise was completed in about 1 hour, and the reaction was continued for 4 hours, then slowly raised to room temperature, and reacted overnight. Wash three times with 300ml of saturated sodium bicarbonate solution, once with 300ml of water, dry over anhydrous sodium sulfate, concentrate to dryness, add 650ml of ethyl acetate, extract with 2N hydrochloric acid (75ml×4), combine the extracts, add 10% Pd / C 0.7 g, normal pressure through H 2 Reduce overnight, filter with celite, neutralize with 20% sodium hydroxide solution, extract with ethyl acetate (300ml×2), combine the organic layers, wash with brine (150ml), dry over anhydrous sodium sulfate, and concentr...

Embodiment 14

[0072] Example 14: Preparation of (S)-dexmedetomidine-L-(+)-tartrate

[0073] L-(+)-tartaric acid (9 g, 60 mmol) was added to a solution of medetomidine (12 g, 60 mmol) in ethanol (250 ml). The suspension was heated to reflux until completely dissolved, then stirred overnight at room temperature, and filtered to obtain a white solid (9 g). The resulting solid was dissolved in isopropanol (200ml) under reflux, stirred overnight at room temperature, and filtered to obtain (13.5g). The obtained solid was refined again by the same method to obtain 8.1 g of solid with a purity of 99.9% and a yield of 77.1%.

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