阅读说明：本技术 一种l-去氧肾上腺素盐酸盐的制备方法 (Preparation method of L-phenylephrine hydrochloride ) 是由 李志锋 王广印 郭朋 朱文峰 于 2020-06-29 设计创作，主要内容包括：本发明涉及一种L-去氧肾上腺素盐酸盐的制备方法。具体本发明公开了一种包含氯化反应、手性还原反应、胺化成盐和重结晶步骤的L-去氧肾上腺素盐酸盐制备方法。本发明制备方法具有原料廉价易得、操作过程简单、经济成本低、产品收率高、产品质量符合中国药典及欧洲药典标准要求等优点。(The invention relates to a preparation method of L-phenylephrine hydrochloride. The invention particularly discloses a preparation method of L-phenylephrine hydrochloride, which comprises the steps of chlorination reaction, chiral reduction reaction, amination salification and recrystallization. The preparation method has the advantages of cheap and easily obtained raw materials, simple operation process, low economic cost, high product yield, product quality meeting the standard requirements of Chinese pharmacopoeia and European pharmacopoeia and the like.)

1. A method of preparing L-phenylephrine hydrochloride, the method comprising:

step 1: chlorinating acetophenone in an inert solvent with a chlorinating agent to form 2-chloro-3' -hydroxyacetophenone;

step 2: carrying out chiral reduction reaction on 2-chloro-3' -hydroxyacetophenone in an inert solvent under the action of a chiral catalyst and borane to form (R) -3- (2-chloro-1-hydroxy-ethyl) phenol;

and step 3: firstly, performing a methylaminoation reaction on (R) -3- (2-chloro-1-hydroxy-ethyl) phenol and a methylamine solution in an inert solvent to form a crude product of L-phenylephrine; then, salifying the L-phenylephrine crude product and a hydrochloric acid solution to obtain an L-phenylephrine hydrochloride crude product; and secondly, recrystallizing or chirally resolving the crude L-phenylephrine hydrochloride into salt, thereby obtaining the L-phenylephrine hydrochloride.

2. The method according to claim 1, wherein in step 1, the chlorinating reagent is sulfuryl chloride or oxalyl chloride.

3. The method of claim 1, wherein in step 2, the chiral catalyst is (1R,2S) -1-amino-2-indanol.

4. The preparation method of claim 1, wherein in the step 2, the equivalent ratio of the 2-chloro-3' -hydroxyacetophenone to the chiral catalyst is 1 (0.05 to 0.20).

5. The preparation method according to claim 1, wherein in the step 2, the equivalent ratio of the 2-chloro-3' -hydroxyacetophenone to the borane is 1 (0.8 to 1.1).

6. The method of claim 1, wherein the step 2 comprises the steps of:

2.1: mixing a tetrahydrofuran solution of a chiral catalyst with a tetrahydrofuran solution of borane, wherein the obtained mixture is directly used in the next step without treatment;

2.2: a tetrahydrofuran solution of 2-chloro-3' -hydroxyacetophenone and a tetrahydrofuran solution of borane are added to the mixture obtained in the above step and subjected to a chiral reduction reaction, thereby forming (R) -3- (2-chloro-1-hydroxy-ethyl) phenol.

7. The method of claim 6, wherein in step 2.2,

simultaneously adding a tetrahydrofuran solution of 2-chloro-3' -hydroxyacetophenone and a tetrahydrofuran solution of borane into the mixture obtained in the step; or

Adding a tetrahydrofuran solution of 2-chloro-3' -hydroxyacetophenone into the mixture obtained in the step, and adding a tetrahydrofuran solution of borane; or

Adding a tetrahydrofuran solution of borane into the mixture obtained in the step, and then adding a tetrahydrofuran solution of 2-chloro-3' -hydroxyacetophenone.

8. The method according to claim 1, wherein in the step 3, the recrystallization comprises the steps of: dissolving the L-phenylephrine hydrochloride crude product in isopropanol, cooling to room temperature, and standing for crystallization to obtain the L-phenylephrine hydrochloride.

9. The preparation method of claim 1, wherein in the step 3, the chiral resolution into salt comprises the steps of:

(a) treating the crude product of L-phenylephrine hydrochloride with alkali to obtain a free crude product of L-phenylephrine hydrochloride;

(b) stirring the L-phenylephrine crude product obtained in the step (a) and D-tartaric acid to form salt, thereby obtaining L-phenylephrine D-tartrate;

(c) treating the L-phenylephrine D-tartrate obtained in step (b) with ammonia to obtain free L-phenylephrine; and

(d) salifying the L-phenylephrine obtained in step (c) with hydrochloric acid to obtain L-phenylephrine hydrochloride.

10. The method according to claim 9, wherein in the step (b), the crude L-phenylephrine obtained in the step (a) is mixed with methanol, D-tartaric acid is added at 55-65 ℃ and stirred for 1-2 hours, and then the temperature is reduced to 0-5 ℃ to precipitate a solid, thereby obtaining L-phenylephrine D-tartrate.

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a preparation method of L-phenylephrine hydrochloride.

Background

The L-phenylephrine hydrochloride is an adrenoceptor agonist and is mainly used for paroxysmal supraventricular tachycardia, mydriasis examination, and prevention and treatment of symptoms such as hypotension caused by spinal anesthesia, general anesthesia and the like.

The chemical structural formula is as follows:

as an optically active drug, L-phenylephrine hydrochloride is reported to be synthesized mainly by two methods, namely racemate resolution and asymmetric catalytic hydrogenation. The racemate resolution method has the disadvantages of complex steps, difficult precipitation of crystals, difficult treatment of mother liquor in each step, low yield, serious environmental pollution, low optical purity of products, and the like, and is not favorable for amplifying production factors, and qualified products can be obtained only by purifying and refining for multiple times. The asymmetric catalytic hydrogenation method has the disadvantages of using expensive chiral metal catalyst, high-pressure hydrogenation special equipment, harsh reaction conditions and the like.

Disclosure of Invention

The invention aims to provide a preparation method of L-phenylephrine hydrochloride, which is suitable for industrial production and mainly overcomes the defects in the prior art.

The invention provides a preparation method of L-phenylephrine hydrochloride, which comprises the following steps:

step 1: chlorinating acetophenone in an inert solvent with a chlorinating agent to form 2-chloro-3' -hydroxyacetophenone;

step 2: carrying out chiral reduction reaction on 2-chloro-3' -hydroxyacetophenone in an inert solvent under the action of a chiral catalyst and borane to form (R) -3- (2-chloro-1-hydroxy-ethyl) phenol;

and step 3: firstly, performing a methylaminoation reaction on (R) -3- (2-chloro-1-hydroxy-ethyl) phenol and a methylamine solution in an inert solvent to form a crude product of L-phenylephrine; then, salifying the L-phenylephrine crude product and a hydrochloric acid solution to obtain an L-phenylephrine hydrochloride crude product; and secondly, recrystallizing or chirally resolving the crude L-phenylephrine hydrochloride into salt, thereby obtaining the L-phenylephrine hydrochloride.

In a preferred embodiment, in step 1, the inert solvent is selected from the group consisting of: dichloromethane, chloroform, tetrahydrofuran, or combinations thereof.

In a preferred example, in the step 1, the chlorinating reagent is sulfuryl chloride or oxalyl chloride.

In a preferred embodiment, the purity of the 2-chloro-3' -hydroxyacetophenone obtained in the step 1 is more than 95%; preferably, it exceeds 98%.

In a preferred embodiment, in the step 1, after the chlorination reaction is finished, the reaction mixture is cooled to 0-5 ℃, and then water is added for quenching, so that an organic phase is separated and concentrated to obtain a crude product; dissolving the crude product in ethyl acetate, adding petroleum ether, stirring at 0-10 ℃ for crystallization, collecting crystals and drying to obtain the 2-chloro-3' -hydroxyacetophenone.

In a preferred embodiment, the step 1 is: dissolving acetophenone in inert solvent, and then dripping a chlorinating agent to perform chlorination reaction, thereby forming 2-chloro-3' -hydroxyacetophenone.

In a preferred example, in the step 1, the temperature is between 0 and 10 ℃ when the chlorinating agent is added dropwise.

In a preferred embodiment, in the step 1, the chlorination reaction is carried out at 20-25 ℃.

In a preferred embodiment, in the step 2, the chiral catalyst is (1R,2S) -1-amino-2-indanol.

In a preferred embodiment, in the step 2, the equivalent ratio of the 2-chloro-3' -hydroxyacetophenone to the chiral catalyst is 1 (0.05-0.20).

In a preferred embodiment, in the step 2, the equivalent ratio of the 2-chloro-3' -hydroxyacetophenone to the borane is 1 (0.8-1.1).

In a preferred embodiment, in the step 2, the chiral reduction reaction is performed at 0-30 ℃.

In a preferred embodiment, in the step 2, the inert solvent is tetrahydrofuran.

In a preferred embodiment, the step 2 includes the following steps:

2.1: mixing a tetrahydrofuran solution of a chiral catalyst with a tetrahydrofuran solution of borane, wherein the obtained mixture is directly used in the next step without treatment;

2.2: a tetrahydrofuran solution of 2-chloro-3' -hydroxyacetophenone and a tetrahydrofuran solution of borane are added to the mixture obtained in the above step and subjected to a chiral reduction reaction, thereby forming (R) -3- (2-chloro-1-hydroxy-ethyl) phenol.

In a preferred embodiment, in the step 2.1, the equivalent ratio of the chiral catalyst to the borane is 0.5: 1.

In a preferred embodiment, in the step 2.2, the equivalent ratio of the 2-chloro-3' -hydroxyacetophenone to the borane is 1: 0.7.

In a preferred embodiment, in step 2.2,

simultaneously adding a tetrahydrofuran solution of 2-chloro-3' -hydroxyacetophenone and a tetrahydrofuran solution of borane into the mixture obtained in the step; or

Adding a tetrahydrofuran solution of 2-chloro-3' -hydroxyacetophenone into the mixture obtained in the step, and adding a tetrahydrofuran solution of borane; or

Adding a tetrahydrofuran solution of borane into the mixture obtained in the step, and then adding a tetrahydrofuran solution of 2-chloro-3' -hydroxyacetophenone.

In a preferred example, in the step 2.2, a tetrahydrofuran solution of 2-chloro-3' -hydroxyacetophenone and a tetrahydrofuran solution of borane are simultaneously added to the mixture obtained in the above step. Preferably at 0-5 ℃ or at 20-25 ℃.

In a preferred embodiment, in the step 2.2, a tetrahydrofuran solution of 2-chloro-3' -hydroxyacetophenone is added to the mixture obtained in the above step at 0-5 ℃, and a tetrahydrofuran solution of borane is added at 20-25 ℃.

In a preferred example, in the step 2.2, a tetrahydrofuran solution of borane is added to the mixture obtained in the above step, and a tetrahydrofuran solution of 2-chloro-3' -hydroxyacetophenone is added. Preferably at 0-5 ℃ or at 20-25 ℃.

In a preferred example, in the step 2, after the chiral reduction reaction is completed, methanol is added to the reaction mixture, the mixture is stirred and concentrated, then the obtained concentrate is stirred and separated from an organic phase (such as dichloromethane or ethyl acetate) and an aqueous phase, the organic phase is collected and concentrated, and thus (R) -3- (2-chloro-1-hydroxy-ethyl) phenol is obtained.

In a preferred embodiment, in step 3, the inert solvent is methanol.

In a preferable example, in the step 3, the methylamine solution is a methylamine aqueous solution, a methylamine methanol solution, a methylamine ethanol solution or a methylamine tetrahydrofuran solution.

In a preferred example, in the step 3, the hydrochloric acid solution is a hydrochloric acid methanol solution.

In a preferred example, in the step 3, the equivalent ratio of the (R) -3- (2-chloro-1-hydroxy-ethyl) phenol to methylamine is 1: 11.

In a preferred embodiment, in the step 3, the methylamine reaction is carried out at 30-40 ℃.

In a preferred embodiment, in the step 3, the recrystallization includes the steps of: the crude L-phenylephrine hydrochloride is dissolved in isopropanol (e.g., at 55-65 deg.C), and then cooled to room temperature for crystallization by standing to obtain L-phenylephrine hydrochloride.

In a preferred embodiment, in the step 3, the chiral resolution to form a salt includes the steps of:

(a) treating the crude L-phenylephrine hydrochloride with a base (e.g., sodium hydroxide or potassium hydroxide) to obtain a crude free L-phenylephrine hydrochloride;

(b) stirring the L-phenylephrine crude product obtained in the step (a) and D-tartaric acid to form salt, thereby obtaining L-phenylephrine D-tartrate;

(c) treating the L-phenylephrine D-tartrate obtained in step (b) with ammonia to obtain free L-phenylephrine; and

(d) salifying the L-phenylephrine obtained in step (c) with hydrochloric acid to obtain L-phenylephrine hydrochloride.

In a preferable example, in the step (b), the crude L-phenylephrine obtained in the step (a) is mixed with methanol, then D-tartaric acid is added at 55-65 ℃ to stir for 1-2 hours, and then the temperature is reduced to 0-5 ℃ to precipitate a solid, so that L-phenylephrine D-tartrate is obtained.

In a preferred embodiment, the chemical purity of the L-phenylephrine hydrochloride obtained in the step 3 is more than 99.0%, and the chiral purity is more than 99.0%.

It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.

Detailed Description

The inventor finds a preparation method of L-phenylephrine hydrochloride through long-term and intensive research. The method has the advantages of cheap and easily-obtained raw materials, simple operation process, low economic cost, high product yield, high product quality and the like, is particularly suitable for large-scale production, and has very important significance for industrial production of the L-phenylephrine hydrochloride. Wherein, the catalyst used in the chiral reduction step is prepared by cheap and easily available (1R,2S) -1-amino-2-indanol and borane tetrahydrofuran solution, and is directly used in the chiral reduction reaction step without separation.

The invention provides a preparation method of L-phenylephrine hydrochloride, which comprises the following steps:

step 1: chlorinating acetophenone in an inert solvent with a chlorinating agent to form 2-chloro-3' -hydroxyacetophenone;

step 2: carrying out chiral reduction reaction on 2-chloro-3' -hydroxyacetophenone in an inert solvent under the action of a chiral catalyst and borane to form (R) -3- (2-chloro-1-hydroxy-ethyl) phenol;

and step 3: firstly, performing a methylaminoation reaction on (R) -3- (2-chloro-1-hydroxy-ethyl) phenol and a methylamine solution in an inert solvent to form a crude product of L-phenylephrine; then, salifying the L-phenylephrine crude product and a hydrochloric acid solution to obtain an L-phenylephrine hydrochloride crude product; and secondly, recrystallizing or chirally resolving the crude L-phenylephrine hydrochloride into salt, thereby obtaining the L-phenylephrine hydrochloride.

In the invention, the chiral optical purity of the final product is controlled by the chiral reduction reaction in the step 2 and the methods of methylamine formation, salt formation crystallization or chiral resolution after dissociation and salt formation again in the step 3 so as to reach the required standard.

In the invention, the chiral catalyst used in the step 2 is prepared by the (1R,2S) -1-amino-2-indanol and the borane tetrahydrofuran solution without separation, and the solution is directly used in the reaction process.

In the invention, the materials in the operation process of the step 2 can be added in different sequences and at different temperatures.

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight. The reagents and starting materials used in the present invention are commercially available.

In the present invention, the room temperature is generally 20 to 30 ℃.

In the present invention, TFA represents trifluoroacetic acid.

In the present invention, DEA represents diethylamine.