CN107879979B

CN107879979B - Preparation method of dexmedetomidine

Info

Publication number: CN107879979B
Application number: CN201711029982.7A
Authority: CN
Inventors: 叶伟平; 费安杰; 周章涛; 尹志媛; 郭陆川; 黄萍; 谢阳银
Original assignee: Guangdong Raffles Pharmatech Co ltd
Current assignee: Guangdong Raffles Pharmatech Co ltd
Priority date: 2017-10-27
Filing date: 2017-10-27
Publication date: 2020-08-25
Anticipated expiration: 2037-10-27
Also published as: CN107879979A

Abstract

The invention discloses a preparation method of dexmedetomidine, which comprises the following steps: carrying out methylation reaction on 5- (2, 3-dimethylphenyl) -1-triphenylmethyl-1H-imidazole and MeI under the action of a phase transfer catalyst; removing the trityl protecting group by using concentrated hydrochloric acid to obtain dexmedetomidine; the synthesis cost is reduced; meanwhile, harsh reaction conditions are avoided, the reaction conditions are simple, dexmedetomidine with high chemical and optical purity can be prepared, the process operability is strong, the industrial production needs are facilitated, the environmental protection pressure is reduced, in addition, the synthetic route is short, the generation of some process impurities can be avoided, and the pressure of the purification of the final product is reduced.

Description

Preparation method of dexmedetomidine

Technical Field

The invention relates to the field of organic chemical synthesis, and in particular relates to a preparation method of dexmedetomidine.

Background

Dexmedetomidine (dexmedetomidine) is an alpha 2-adrenergic receptor agonist useful for sedation of tracheal intubation and mechanical ventilation in surgical patients undergoing general anesthesia. In recent years, dexmedetomidine has been widely used in clinical anesthesia.

Currently, there are two main routes for the synthesis of this drug.

The first synthetic route is as follows:

the second synthetic route is as follows:

as can be seen, both routes are to synthesize the racemic product medetomidine first, and then to split it with L-tartaric acid to obtain optically pure dexmedetomidine. The yield of the resolution process is generally 20-30%.

In summary, the existing synthesis method of optically pure dexmedetomidine mainly relies on resolution, has low yield and poor atom economy, thus having high cost and much discharge of three wastes.

Disclosure of Invention

Aiming at the defects of the prior art and overcoming the defect that the synthesis of dexmedetomidine needs to be split, the invention provides a process route for directly synthesizing dexmedetomidine through asymmetric catalysis.

The invention is realized by the following technical scheme:

a preparation method of dexmedetomidine comprises the following steps:

carrying out methylation reaction on 5- (2, 3-dimethylphenyl) -1-triphenylmethyl-1H-imidazole and MeI under the action of a phase transfer catalyst;

removing the trityl protecting group by using concentrated hydrochloric acid to obtain dexmedetomidine;

the synthetic route is as follows:

。

further, the phase transfer catalyst is a biguanide catalyst.

Further, the biguanide catalyst has the structural formula:

，

wherein, Ar group is aromatic substituent, and R group is benzyl substituent or other bulky steric hindrance alkyl substituent.

Further, the biguanide catalyst has the structural formula:

，

Further, the Ar group is one of phenyl, p-methylphenyl, 3, 5-dimethylphenyl, p-methoxyphenyl, 3, 5-di-tert-butylphenyl, 1-naphthyl or 2-naphthyl.

Further, the R group is one of benzyl, p-methylbenzyl, 3, 5-dimethylbenzyl, p-methoxybenzyl, 3, 5-di-tert-butylbenzyl, 1-naphthylmethylene, 2-naphthylmethylene, tert-butyl or isopropyl.

Furthermore, the 5- (2, 3-dimethylphenyl) -1-triphenylmethyl-1H-imidazole is prepared by taking (2, 3-dimethylphenyl) (1H-imidazole-4-yl) ketone as a raw material through reduction and substitution reaction;

the synthetic route is as follows:

。

compared with the prior art, the invention has the following advantages:

the synthesis cost is reduced; meanwhile, harsh reaction conditions are avoided, the reaction conditions are simple, dexmedetomidine with high chemical and optical purity can be prepared, the process operability is strong, the industrial production needs are facilitated, the environmental protection pressure is reduced, in addition, the synthetic route is short, certain process impurities can be avoided, and the pressure for purifying the final product is reduced.

Detailed Description

The following detailed description of the preferred embodiments of the present invention is provided to enable those skilled in the art to more clearly understand the advantages and features of the present invention and to clearly define the scope of the present invention.

Example 1

Step 1:

(2, 3-d-dimethylphenyl) (1H-imidazol-4-yl) methanol

Adding 60 g of (2, 3-dimethylphenyl) (1H-imidazol-4-yl) methanone into a 1000 mL four-mouth bottle, adding 300mL of methanol, adding 34.53 g of sodium borohydride into an ice-ethanol bath at a controlled temperature in batches, controlling the temperature to be below 0 ℃, generating gas and releasing heat, and after the sodium borohydride is added for 20 min, sampling TLC (thin layer chromatography) to show that the reaction is complete for post-treatment: controlling the temperature below 10 ℃, adding 100 mL of ice water for quenching, adding 1200 mL of ice water, stirring in an ice-ethanol bath (0 ℃) for 30 min to separate out a light yellow solid, performing suction filtration, removing filtrate, adding 200 mL of water to rinse a filter cake, performing suction filtration, removing filtrate, adding the filter cake into a vacuum drying oven, placing the vacuum drying oven in a vacuum drying condition: the temperature is 60 ℃, the vacuum is-0.09 MPa, the time is 10 h, and yellow solid is obtained after drying.

Step 2:

taking a 1000 mL four-mouth bottle, sequentially adding 55 g of (2, 3-d-dimethylphenyl) (1H-imidazol-4-yl) methanol and 220mL of isopropanol (4.0 vol.), dropwise adding 275 mL of concentrated hydrochloric acid (5.0 vol.), releasing heat, controlling the temperature to be below 41 ℃, heating after the reaction solution is cooled to room temperature (29 ℃), heating the reaction solution to 60 ℃, and then carrying out heat preservation reaction for 4 hours, wherein TLC shows that the reaction is complete. And (3) post-treatment: adding the reaction solution in a four-mouth bottle into 1250 mL of ice water, stirring, adding sodium carbonate solid to adjust the pH value to 7-8, performing suction filtration, adding 400mL of water into a filter cake, stirring for 20 minutes, performing suction filtration, discarding the filtrate obtained in the two times, putting the filter cake into a vacuum drying oven, and drying for 11 hours under the conditions that the oven temperature is 60 ℃, the vacuum is-0.09 MPa, so as to obtain a light yellow solid.

And step 3:

a1000 mL four-necked flask was charged with 45 g of the intermediate obtained in the previous step, followed by 500 mL of acetonitrile and 100 g of anhydrous potassium carbonate, and then 90 g of triphenylchloromethane was added in portions. After the reaction is finished, filtering, and desolventizing the filtrate for direct use in the next step.

And 4, step 4:

the residue obtained in the previous step was dissolved in 2000 ml of toluene, and then 5 g of a phase transfer catalyst (shown below) was added. Then 20 g of 1,5, 7-triazabicyclo (4.4.0) dec-5-ene were added. Then, 15 g of methyl iodide was added thereto, and the mixture was stirred at room temperature for 12 hours. After the reaction was completed, 1000 ml of water was added, and the mixture was separated. The organic phase is desolventized and recrystallized from 700 ml of ethyl acetate. The optical purity of the obtained product is 99.5%.

The phase transfer catalyst has the structure as follows:

and 5:

the crystals obtained in the previous step were dissolved in 1500 ml of methanol, and 10 ml of concentrated hydrochloric acid was added thereto and heated under reflux for 4 hours. Cooled to 0 ℃ and filtered to obtain white crystals. The product was recrystallized once more with methanol and the optical purity was found to be 99.9%.

Example 2

And 4, step 4:

the residue obtained in the previous step was dissolved in 2000 ml of toluene, and then 2 g of a phase transfer catalyst (structure shown below) was added. Then 20 g of 1,5, 7-triazabicyclo (4.4.0) dec-5-ene were added. Then, 15 g of methyl iodide was added thereto, and the mixture was stirred at room temperature for 12 hours. After the reaction was completed, 1000 ml of water was added, and the mixture was separated. The organic phase is desolventized and recrystallized from 700 ml of ethyl acetate. The optical purity of the obtained product is 99.7%.

The phase transfer catalyst has the structure as follows:

example 3

And 4, step 4:

the residue obtained in the previous step was dissolved in 2000 ml of toluene, and then 3 g of a phase transfer catalyst (structure shown below) was added. Then 20 g of 1,5, 7-triazabicyclo (4.4.0) dec-5-ene were added. Then, 15 g of methyl iodide was added thereto, and the mixture was stirred at room temperature for 12 hours. After the reaction was completed, 1000 ml of water was added, and the mixture was separated. The organic phase is desolventized and recrystallized from 700 ml of ethyl acetate. The optical purity of the obtained product is 99.0%.

The phase transfer catalyst has the structure as follows:

the above description is only a preferred embodiment of the present invention, and not intended to limit the scope of the present invention, and all modifications of equivalent structures and equivalent processes, which are made by the present specification, or directly or indirectly applied to other related technical fields, are included in the scope of the present invention.

Claims

1. A method for preparing dexmedetomidine is characterized in that: the method comprises the following steps:

carrying out methylation reaction on 5- (2, 3-dimethylphenyl) -1-triphenylmethyl-1H-imidazole and MeI under the action of a phase transfer catalyst; removing the trityl protecting group by using concentrated hydrochloric acid to obtain dexmedetomidine;

the synthetic route is as follows:

the phase transfer catalyst is a biguanide catalyst;

the structural formula of the biguanide catalyst is as follows:

andor or

Wherein, Ar group is aromatic substituent, R group is benzyl substituent or other bulky steric hindrance alkyl substituent;

the Ar group is one of phenyl, p-methylphenyl, 3, 5-dimethylphenyl, p-methoxyphenyl, 3, 5-di-tert-butylphenyl, 1-naphthyl or 2-naphthyl;

the R group is one of benzyl, p-methylbenzyl, 3, 5-dimethylbenzyl, p-methoxybenzyl, 3, 5-di-tert-butylbenzyl, 1-naphthylmethylene, 2-naphthylmethylene, tert-butyl or isopropyl.