CN113735760A - Preparation method of ropivacaine hydrochloride - Google Patents

Abstract

The invention discloses a preparation method of ropivacaine hydrochloride, which comprises the following specific steps: 1) in the presence of a reducing agent and an aprotic solvent, (S) -piperidine-2-formic acid and propionaldehyde undergo a reductive amination reaction to obtain an intermediate 1; 2) in thatN,N-subjecting the intermediate 1 obtained in step 1) to an acylation reaction with an acylating agent in the presence of dimethylformamide and an aprotic solvent to obtain an intermediate 2; 3) in thatN,NCarrying out a condensation reaction on the intermediate 2 obtained in the step 2) and 2, 6-dimethylaniline in the presence of dimethylformamide under an alkaline condition to obtain an intermediate 3; 4) salifying the intermediate 3 obtained in the step 3) with hydrochloric acid to obtain a crude ropivacaine hydrochloride product; 5) the crude product of the ropivacaine hydrochloride is purified to obtain a refined product of the ropivacaine hydrochloride. The purity of the product prepared by the method is more than 99.99%, and the synthesis process has the advantages of mild reaction conditions, simple preparation process, low cost, safety, environmental protection and suitability for industrial production.

Description

Preparation method of ropivacaine hydrochloride

Technical Field

The invention belongs to the technical field of chemistry, particularly relates to the technical field of synthesis of a novel long-acting amide local anesthetic, and particularly relates to a preparation method of ropivacaine hydrochloride.

Background

Ropivacaine (Ropivacaine) is a pure levorotatory long-acting amide analgesic and local anesthetic, is suitable for surgical anesthesia, and has the dual effects of anesthesia and analgesia by inhibiting nerve cell sodium ion channels like other local anesthetics, so that the nerve excitation and conduction are blocked, the surgical anesthesia can be generated at a large dose, and the sensory block (analgesia) is generated at a small dose and is only accompanied with limited non-progressive motor nerve block; ropivacaine, developed and widely popularized by AstraZeneca (AstraZeneca plc) in 1996, is the first new type of pure levorotatory long-acting amide local anesthetic in the world, and was approved in the united states 10 months in 1996, and then subsequently approved in the united kingdom, france, and the like, successively, and by 3 months in 2005, ropivacaine was approved in china.

Ropivacaine belongs to a long-acting amide local anesthetic, and has good curative effect in the aspect of surgical anesthesia, so that the chemical synthesis method of ropivacaine is emphasized, and the synthesis method of ropivacaine at present mainly comprises the following routes:

route one:

the first route is published by Chinese patent CN201410263792.1, 2-piperidinecarboxylic acid is used as an initial material, and the target product ropivacaine hydrochloride is finally prepared by sequentially carrying out reactions such as acylation reaction, condensation, alkylation, resolution, salification and the like.

And a second route:

route two, reported in 2006 as "synthesis of ropivacaine by triphosgene method" in journal of synthetic chemistry, volume 14, phase 4, using triphosgene to prepare acid chloride, but triphosgene is dangerous in storage and post-treatment and is not suitable for industrial production.

And a third route:

the third route is that L-piperidine-2-formic acid is used as a starting material to react with an acylating reagent to obtain L-piperidine-2-formyl chloride, then the L-piperidine-2-formyl chloride reacts with 2, 6-dimethylaniline to prepare (S) -N- (2, 6-dimethylphenyl) piperidine-2-formamide, and then the L-piperidine-2-formamide reacts with bromopropane to obtain ropivacaine.

And a fourth route:

US4695576 also discloses a synthetic method for preparing ropivacaine, as shown in the fourth route, in which piperidine-2-carboxylic acid is used as the starting material, and the L-piperidine-2-carboxylic acid is obtained by resolution, and then the target product ropivacaine is obtained by acylation, condensation and alkylation.

And a fifth route:

chinese patent CN201710470848.4 discloses a method for preparing ropivacaine hydrochloride, as described in the fifth route, the method uses 2-piperidinecarboxylic acid as a starting material, introduces hydrochloric acid gas into a toluene and chloroform solution to form salt, the reaction is heterogeneous, the salt forming effect is poor, a self-condensation byproduct exists, and then the target product ropivacaine is obtained through acylation, condensation and alkylation.

Route six:

chinese patent 201910029895.4 discloses a method for preparing and purifying ropivacaine hydrochloride intermediate, as shown in the sixth route, which uses L-piperidine-2-formic acid hydrochloride as starting material, and obtains intermediate with purity as low as 94% through acylation and condensation in toluene, and refining with low boiling point solvent such as ethyl ether and isopropyl ether, which is not suitable for industrial production.

In summary, the preparation process for producing ropivacaine hydrochloride listed in the prior art has certain defects in industrial production, so that a new green and environment-friendly scheme for synthesizing ropivacaine is urgently found.

Disclosure of Invention

Aiming at solving the problems in the prior art, the invention aims at the defects in the prior art and provides a preparation method of ropivacaine hydrochloride, which is easier to operate, higher in purity of the obtained product and higher in yield.

The technical concept of the invention is as follows:

the preparation method of the invention takes single chiral (S) -piperidine-2-formic acid as an initial material to directly carry out reductive amination reaction with propionaldehyde, and because amido is an active group, the protection and deprotection of amido can be avoided, the subsequent resolution can be avoided, simultaneously the generation of quaternary ammonium salt impurities can be inhibited, and the final product is obtained through amidation, salification and purification.

The technical scheme of the invention is as follows:

a preparation method of ropivacaine hydrochloride comprises the following synthetic route:

the preparation method comprises the following specific steps:

1) in the presence of a reducing agent and an aprotic solvent, carrying out reductive amination reaction on (S) -piperidine-2-formic acid and propionaldehyde to obtain an intermediate 1, namely (S) -1-n-propylpiperidine-2-formic acid;

2) in the presence of N, N-dimethylformamide and an aprotic solvent, carrying out acylation reaction on the intermediate 1 obtained in the step 1) and an acylation reagent to obtain an intermediate 2, namely (S) -1-N-propylpiperidine-2-formyl chloride;

3) carrying out condensation reaction on the intermediate 2 obtained in the step 2) and 2, 6-dimethylaniline in the presence of N, N-dimethylformamide under alkaline conditions to obtain an intermediate 3, namely (-) - (S) -N- (2, 6-dimethylphenyl) -1-N-propylpiperidine-2-formamide;

4) salifying the intermediate 3 obtained in the step 3) with hydrochloric acid to obtain a crude ropivacaine hydrochloride product;

5) the crude product of the ropivacaine hydrochloride is purified to obtain a refined product of the ropivacaine hydrochloride.

Preferably, the first and second electrodes are formed of a metal,

in the step 1), the molar ratio of (S) -piperidine-2-formic acid to propionaldehyde is 1: 2.0-3.0, the reaction time is 6-12 hours, and the reaction temperature is 25-55 ℃;

in the step 2), the molar ratio of the reaction of the intermediate 1 and the acylating reagent is 1: 1.0-1.2, the reaction time is 2-8 hours, and the reaction mode is reflux reaction at 40 ℃;

in the step 3), the molar ratio of the intermediate 2 to the 2, 6-dimethylaniline is 1: 1.0-1.3, the reaction time is 0.5-5 hours, and the reaction temperature is 20-55 ℃;

in the step 4), the molar ratio of the intermediate 3 to the hydrochloric acid is 1: 1.2-2.0, the reaction time is 1-5 hours, and the reaction temperature is 40-70 ℃.

In the step 1), the reducing agent is any one of sodium borohydride acetate, sodium cyanoborohydride and sodium borohydride.

In the step 1) and the step 2), the aprotic solvent is selected from one or more of dichloromethane, acetone, chloroform, tetrahydrofuran, acetonitrile, DMF and DMSO.

In the step 2), the acylating reagent is selected from one of thionyl chloride, phosphorus trichloride and phosphorus pentachloride.

In the step 3), the alkali is selected from one of sodium hydroxide, sodium carbonate, potassium carbonate and potassium hydroxide.

The hydrochloric acid in the step 4) is concentrated hydrochloric acid.

The purification mode in the step 5) is selected from a mixed solvent of isopropanol v, ethanol v ═ 2: and 3, recrystallizing.

More preferably still, the first and second liquid crystal compositions are,

in the step 1), the molar ratio of (S) -piperidine-2-carboxylic acid to propionaldehyde is 1: 3, the reaction time is preferably 10 hours, the reaction temperature is preferably 35 ℃, the reducing agent is sodium cyanoborohydride or sodium acetate borohydride, and the aprotic solvent is preferably dichloromethane;

in the step 2), the molar ratio of the reaction of the intermediate 1 and the acylating reagent is 1: 1.1, the reaction condition is reflux reaction for 4 hours at 40 ℃, the acylating agent is preferably thionyl chloride, and the aprotic solvent is preferably dichloromethane;

in the step 3), the molar ratio of the intermediate 2 to the 2, 6-dimethylaniline is 1: 1.2; the reaction time is preferably 2 hours, the reaction temperature is preferably 45 ℃, and the alkali is preferably potassium hydroxide or potassium carbonate;

in the step 4), the molar ratio of the intermediate 3 to the hydrochloric acid is 1:1.3, the reaction time is preferably 2 hours, and the reaction temperature is preferably 50 ℃.

Compared with the prior art, the method of the invention takes the single chiral (S) -piperidine-2-formic acid as the starting material, can avoid the subsequent resolution, in addition, because the amido is an active group, the starting material (S) -piperidine-2-formic acid with the single chiral is adopted to carry out reductive amination reaction with propionaldehyde, thereby not only avoiding the protection and deprotection of the amido, but also inhibiting the generation of new quaternary ammonium salt impurities; in addition, the synthesis process has mild conditions, short steps, easy control, no strong toxicity, strong irritation chemical solvent reagent and no reaction conditions such as high temperature, strong acid and alkali, and the like, so the invention finds a new green and environment-friendly synthesis method for preparing the ropivacaine hydrochloride. The purity of the finally obtained ropivacaine is up to more than 99.99 percent, and the yield is up to more than 78 percent.

Drawings

FIG. 1 is the NMR hydrogen spectrum of ropivacaine hydrochloride of example 1.

FIG. 2 is the nuclear magnetic resonance carbon spectrum of ropivacaine hydrochloride of example 1.

FIG. 3 is a mass spectrum of ropivacaine hydrochloride of example 1.

FIG. 4 is an HPLC chromatogram of ropivacaine hydrochloride of example 1.

Detailed Description

The invention is further described below with reference to specific embodiments.

In order to specifically describe the present invention and to assist those skilled in the art in further understanding the present invention, the following examples have been selected to describe the present invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention.

EXAMPLE 1 preparation of ropivacaine hydrochloride

Step 1: preparation of intermediate 1

(S) -piperidine-2-carboxylic acid (100.00g,0.77mol), propionaldehyde (104.32g,2.32mol) and dichloromethane (800mL) were added to a 2000mL reaction flask, the air in the reaction flask was replaced with nitrogen, sodium cyanoborohydride (111.90g,2.30mol) was added, the reaction was carried out at 35 ℃ for 10 hours, after completion of the reaction, the reaction was quenched with a saturated aqueous sodium bicarbonate solution (500mL), the organic phase was separated, the aqueous phase was extracted with dichloromethane (500 mL. times.2), the organic phases were combined, dried over anhydrous magnesium sulfate, and concentrated at 40 ℃ to 45 ℃ under reduced pressure to give 125g of intermediate 1, with a yield of 94.3%.

Step 2: preparation of intermediate 2

Adding the intermediate 1(100.00g,0.58mol), dichloromethane (600mL) and N, N-dimethylformamide (2mL) into a 2000mL reaction bottle, cooling to 5 ℃ in an ice water bath, slowly dropwise adding thionyl chloride (76.42g,0.64mol), controlling the internal temperature to be less than or equal to 10 ℃, removing the ice water bath after the addition is finished, naturally returning to room temperature, heating to 40 ℃ in the internal temperature, carrying out reflux reaction for 4 hours, and after the reaction is finished, carrying out reduced pressure concentration to remove dichloromethane and excessive thionyl chloride to obtain an intermediate 2 which is directly used for the next reaction.

And step 3: preparation of intermediate 3

N, N-dimethylformamide (500mL) and potassium hydroxide (81.92g,1.46mol) are added into a reaction bottle of the intermediate 2(111.77g,0.58mol) obtained in the previous step, the mixture is stirred at room temperature for 1 hour, 2, 6-dimethylaniline (84.92g,0.70mol) is added dropwise, after the addition is finished, the temperature is increased to 45 ℃ for reaction for 2 hours, the temperature is reduced to room temperature after the reaction is finished, the reaction solution is poured into 1200mL of ice water, a large amount of white solid is separated out, the mixture is stirred for 1 hour and then filtered, a filter cake is washed with 800mL of water slurry for 1 hour and filtered, and the mixture is dried by air blowing at 60 ℃ for 10 hours to obtain 148g of white solid, and the yield is 92.4%.

And 4, step 4: preparation of ropivacaine hydrochloride crude product

Adding the intermediate 3(100g,0.36mol) and isopropanol (600mL) into a 2000mL reaction bottle, heating to 50 ℃, dropwise adding concentrated hydrochloric acid (47.98g, 0.47mol), preserving heat for 2 hours after the addition is finished, cooling to 0-10 ℃ after the reaction is finished, crystallizing for 3 hours, filtering, leaching a filter cake with isopropanol (50mL), and carrying out vacuum drying at 50 ℃ for 8 hours to obtain 114g of ropivacaine hydrochloride with the yield of 95.1%.

And 5: preparation of ropivacaine hydrochloride refined product

Adding crude ropivacaine hydrochloride (80g, 0.24mol) and 160mL of isopropanol and 240mL of ethanol into a 1000mL reaction bottle respectively, heating and dissolving at 60 ℃, then keeping the temperature for one hour, naturally cooling to room temperature, crystallizing, filtering, washing a filter cake with a small amount of mixed solution, performing suction filtration and drying to obtain a refined ropivacaine hydrochloride 76g with the yield of 95.0%.

The product detection results are as follows:

¹H NMR(500MHz,DMSO-d6)δ＝11.67-10.97(m,1H),10.49-9.92(m,1H),7.10(s,3H),4.64-4.37(m,1H),3.85-3.46(m,1H),3.37(s,2H),3.15-3.02(m,2H),3.02-2.94(m,1H),2.31(t,J＝12.2Hz,1H),2.17(s,6H),1.97-1.61(m,6H),1.61-1.48(m,1H),0.89(t,J＝7.15Hz,3H)；¹³C NMR(125MHz,DMSO-d6)δ＝166.4,134.9,133.7,127.8,126.9,64.8,56.1,51.3,28.5,22.0,21.1,18.0,16.1,10.8；MS:m/z 275.2[M+H]⁺。

EXAMPLE 2 preparation of ropivacaine hydrochloride

Step 1: preparation of intermediate 1

(S) -piperidine-2-carboxylic acid (100.00g,0.77mol), propionaldehyde (104.32g,2.32mol) and dichloromethane (800mL) are added into a 2000mL reaction flask, air in the reaction flask is replaced by nitrogen, then sodium borohydride acetate (380.69g,2.32mol) is added to react for 10 hours at the temperature of 35 ℃, after the reaction is finished, saturated aqueous sodium bicarbonate solution (500mL) is used for quenching, an organic phase is separated, an aqueous phase is extracted by dichloromethane (500mL 2), the organic phases are combined, anhydrous magnesium sulfate is dried, and the temperature of 40-45 ℃ is reduced and concentrated to obtain 110g of intermediate 1, wherein the yield is 83.0%.

Step 2: preparation of intermediate 2

Adding the intermediate 1(100.00g,0.58mol), dichloromethane (600mL) and N, N-dimethylformamide (2mL) into a 2000mL reaction bottle, cooling to an internal temperature of 10 ℃ in an ice water bath, slowly dropwise adding thionyl chloride (76.42g,0.64mol), controlling the internal temperature to be less than or equal to 15 ℃, removing the ice water bath after the addition is finished, naturally returning to room temperature, heating to an internal temperature of 40 ℃, carrying out reflux reaction for 4 hours, and after the reaction is finished, carrying out reduced pressure concentration to remove dichloromethane and excessive thionyl chloride to obtain an intermediate 2, and directly using the intermediate 2 in the next reaction.

And step 3: preparation of intermediate 3

N, N-dimethylformamide (500mL) and potassium carbonate (201.78g,1.46mol) are added into a reaction bottle of the intermediate 2(110.77g,0.58mol) obtained in the previous step, the mixture is stirred at room temperature for 0.5 hour, 2, 6-dimethylaniline (84.92g,0.70mol) is added dropwise, the temperature is raised to 45 ℃ for reaction for 2 hours after the addition is finished, the reaction solution is cooled to room temperature after the reaction is finished, the reaction solution is poured into 1200mL of ice water, a large amount of white solid is separated out, the mixture is stirred for 1 hour and filtered, a filter cake is washed with (800mL) water slurry for 1 hour and filtered, and the mixture is dried by air blowing at 60 ℃ for 10 hours to obtain 136g of white solid, and the yield is 84.9%.

The preparation process of the crude and refined ropivacaine hydrochloride is the same as that of example 1.

Example 2 differs from example 1 in that:

1) the reducing agent used in the preparation of intermediate 1 was different, with example 1 being sodium cyanoborohydride and example 2 being sodium borohydride acetate.

2) The temperature of the intermediate 2 in the preparation process is different, namely 5 ℃ in example 1 and 10 ℃ in example 2;

3) the base used in the preparation of intermediate 3 was different. Example 1 is potassium hydroxide and example 2 is potassium carbonate.

The product of example 2 was identical to that of example 1, confirmed by dot plate control.

The above description is only a few examples of the present invention and does not limit the scope of the present invention, of which example 1 is the preferred example.

Claims (9)

1. The preparation method of ropivacaine hydrochloride is characterized in that the synthetic route is as follows:

the preparation method comprises the following specific steps:

1) in the presence of a reducing agent and an aprotic solvent, carrying out reductive amination reaction on (S) -piperidine-2-formic acid and propionaldehyde to obtain an intermediate 1, namely (S) -1-n-propylpiperidine-2-formic acid;

2) in the presence of N, N-dimethylformamide and an aprotic solvent, carrying out acylation reaction on the intermediate 1 obtained in the step 1) and an acylation reagent to obtain an intermediate 2, namely (S) -1-N-propylpiperidine-2-formyl chloride;

3) carrying out condensation reaction on the intermediate 2 obtained in the step 2) and 2, 6-dimethylaniline in the presence of N, N-dimethylformamide under alkaline conditions to obtain an intermediate 3, namely (-) - (S) -N- (2, 6-dimethylphenyl) -1-N-propylpiperidine-2-formamide;

4) salifying the intermediate 3 obtained in the step 3) with hydrochloric acid to obtain a crude ropivacaine hydrochloride product;

5) the crude product of the ropivacaine hydrochloride is purified to obtain a refined product of the ropivacaine hydrochloride.

2. The method of claim 1, wherein:

in the step 1), the molar ratio of (S) -piperidine-2-formic acid to propionaldehyde is 1: 2.0-3.0, the reaction time is 6-12 hours, and the reaction temperature is 25-55 ℃;

in the step 2), the molar ratio of the reaction of the intermediate 1 and the acylating reagent is 1: 1.0-1.2, the reaction time is 2-8 hours, and the reaction mode is reflux reaction at 40 ℃;

in the step 3), the molar ratio of the intermediate 2 to the 2, 6-dimethylaniline is 1: 1.0-1.3, the reaction time is 0.5-5 hours, and the reaction temperature is 20-55 ℃;

in the step 4), the molar ratio of the intermediate 3 to the hydrochloric acid is 1: 1.2-2.0, the reaction time is 1-5 hours, and the reaction temperature is 40-70 ℃.

3. The preparation method according to claim 1, wherein in the step 1), the reducing agent is any one of sodium borohydride acetate, sodium cyanoborohydride and sodium borohydride.

4. The method according to claim 1), wherein the aprotic solvent is selected from one or more of dichloromethane, acetone, chloroform, tetrahydrofuran, acetonitrile, DMF, and DMSO in the steps 1) and 2).

5. The method according to claim 1, wherein in step 2), the acylating agent is selected from one of thionyl chloride, phosphorus trichloride and phosphorus pentachloride.

6. The preparation method according to claim 1, wherein in the step 3), the alkali is selected from one of sodium hydroxide, sodium carbonate, potassium carbonate and potassium hydroxide.

7. The method according to claim 1, wherein the hydrochloric acid in the step 4) is concentrated hydrochloric acid.

8. The preparation method according to claim 1, wherein the purification mode in the step 5) is selected from a mixed solvent of isopropanol v: ethanol v ═ 2: and 3, recrystallizing.

9. The production method according to any one of claims 1 to 8, characterized in that:

in the step 1), the molar ratio of (S) -piperidine-2-carboxylic acid to propionaldehyde is 1: 3, the reaction time is preferably 10 hours, the reaction temperature is preferably 35 ℃, the reducing agent is sodium cyanoborohydride or sodium acetate borohydride, and the aprotic solvent is preferably dichloromethane;

in the step 2), the molar ratio of the reaction of the intermediate 1 and the acylating reagent is 1: 1.1, the reaction condition is reflux reaction for 4 hours at 40 ℃, the acylating agent is preferably thionyl chloride, and the aprotic solvent is preferably dichloromethane;

in the step 3), the molar ratio of the intermediate 2 to the 2, 6-dimethylaniline is 1: 1.2; the reaction time is preferably 2 hours, the reaction temperature is preferably 45 ℃, and the alkali is preferably potassium hydroxide or potassium carbonate;

in the step 4), the molar ratio of the intermediate 3 to the hydrochloric acid is 1:1.3, the reaction time is preferably 2 hours, and the reaction temperature is preferably 50 ℃.

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