CN112047883B - Preparation method of atracurium besylate - Google Patents

Abstract

The invention belongs to the fields of pharmaceutical chemistry and chemical synthesis, and particularly relates to a preparation method and application of atracurium. The invention provides a method for synthesizing high-purity cis-atracurium besylate. The invention also provides a preparation method of the high-purity refined 1, 5-pentanediol from the raw materials used for synthesizing the high-purity atracurium. The method for synthesizing the atracurium besilate has the following advantages: the method is simple and convenient, has high yield, high conversion rate of raw materials and high purity of products, and is used for industrial production.

Description

Preparation method of atracurium besylate

Technical Field

The invention belongs to the field of pharmaceutical chemistry and chemical synthesis, and particularly relates to atracurium besylate and a preparation method and application thereof.

Background technique

Cisatracurium besylate has no obvious histamine release, little muscle relaxant effect, no accumulation effect, and little cardiovascular response. It also has little dependence on the functions of organs such as the liver and kidneys. It is an ideal medium-acting non-depolarizing muscle relaxant.

Various synthesis methods of cisatracurium besylate have been publicly reported. WO9200965 reported that R-tetrahydropapaverine reacts with pentanediol diacrylate to undergo addition reaction, then is liberated, and further reacts with methyl benzenesulfonate to obtain atracurium besylate, and finally column chromatography is performed to obtain cis-atracurium besylate.

WO2009007946 discloses another synthesis method, wherein monoamine propionate tert-butyl ester reacts with methyl benzenesulfonate to generate monoamine propionate tert-butyl ester quaternary ammonium salt, which is then split to obtain cis-monoamine propionate tert-butyl ester quaternary ammonium salt, which is then hydrolyzed to obtain monoamine propionate quaternary ammonium salt, which is then further reacted with pentanediol to obtain the product cis-atracurium benzenesulfonate. The monoamine propionate quaternary ammonium salt can also be reacted with pentanediol to obtain cis-monoamine propionate pentanediol ester, which is then condensed with another molecule of monoamine propionate quaternary ammonium salt to obtain the product cis-atracurium benzenesulfonate.

The raw materials used in the above patents are all purchased from the market. The pentanediol currently available on the market and used for industrial-scale preparation of products contains a variety of impurities, the main impurities being 1,6-hexanediol, 1-methylpentanediol, 2-methylpentanediol, 3-methylpentanediol, etc. These chemically active impurities can undergo condensation reaction with the raw material compound II under the catalysis of benzenesulfonic acid to generate impurities, which are similar in nature to the product and are not easy to purify.

The synthesis method reported in WO2009007946 has some problems worth noting. Specifically, the conversion of the condensed monoamine propionic acid quaternary ammonium salt raw material is incomplete, and the remaining raw material is not easy to purify; the raw material pentanediol available on the market often contains impurities that can participate in the reaction, resulting in a high content of impurities, requiring complex purification steps to obtain qualified products, and the product quality is unstable; the purification process of various impurities requires a large amount of solvents, causing pollution. The above problems will be more serious in industrial production.

Therefore, it is particularly important to develop a new method for preparing high-purity cis-atracurium besylate with high conversion rate. It is also necessary to develop a method for refining the raw material pentanediol. In addition, the new method needs to meet the requirements of the ESH management system and conform to the higher pursuit and concept of safe, environmentally friendly and green synthesis.

Purpose of the Invention

In order to solve the deficiencies in the prior art, the present invention belongs to the field of pharmaceutical chemistry and chemical synthesis, and specifically relates to a preparation method of cisatracurium besylate.

Technical solutions

In order to achieve the above object, the present invention provides a method for preparing cisatracurium besylate represented by structural formula I, which is achieved by the following reaction formula:

The method comprises the following steps:

The purified 1,5-pentanediol represented by formula III, the compound represented by formula II, and the catalyst benzenesulfonic acid monohydrate represented by formula IV are dissolved in an organic solvent to undergo a condensation reaction to obtain cis-atracurium benzenesulfonate represented by formula I.

Preferably, the organic solvent used in the above condensation reaction is selected from one or a mixture of dichloromethane, chlorobenzene, toluene, xylene, ethyl acetate, methyl acetate, propyl acetate, butyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, acetonitrile, acetone or butanone.

Preferably, the reaction temperature of the condensation reaction is 30-160 degrees Celsius. Further preferably, a desiccant is added to the reaction mixture or the reflux water separation device.

More preferably, the organic solvent used is dichloromethane; more preferably, the reaction temperature of the condensation reaction is the reflux temperature of dichloromethane. More preferably, the reactor is equipped with a reflux water separation device, and a mixture of one or more of molecular sieves, sodium sulfate, magnesium sulfate, calcium chloride, and silica gel is added to the reflux water separation device as a desiccant.

After the reaction is completed, the mixture is cooled to room temperature, benzenesulfonic acid and water-soluble impurities are washed away with water, the dichloromethane layer is concentrated to a small volume under reduced pressure, and then added dropwise to an organic solvent to precipitate a solid, which is then filtered and dried to obtain high-purity atracurium besylate.

The organic solvent used in the above purification process is selected from one or a mixture of toluene, cyclohexane, xylene, chlorobenzene, n-hexane, petroleum ether, n-heptane, methyl tert-butyl ether, isopropyl ether, n-butyl ether, ethyl ether, tetrahydrofuran, methyltetrahydrofuran, ethyl acetate, methyl formate, ethyl formate, methyl acetate, isopropyl acetate, tert-butyl acetate, butyl acetate, ethyl propionate, methyl propionate, methyl benzoate, butyl chloride, chloropentane, chlorocyclopentane, hexyl chloride, chlorocyclohexane, acetone, butanone, pentanone, cyclohexanone, etc.

Another object of the present invention is to provide a method for preparing the refined 1,5-pentanediol, which comprises the following steps:

The crude 1,5-pentanediol of structural formula III and p-nitrobenzoic acid of structural formula V are subjected to a condensation reaction under acid catalysis to obtain a compound of formula VI, and then a hydrolysis reaction is carried out under alkaline conditions to obtain refined 1,5-pentanediol.

Preferably, the acid is selected from one or more of benzenesulfonic acid, methanesulfonic acid, sulfuric acid, etc.

Preferably, the alkaline condition is the presence of one or more of sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate.

After purification, the purity of 1,5-pentanediol is as high as 99.8%, and the content of a single impurity is controlled below 0.06%, effectively controlling the generation of impurities from the source.

Beneficial Effects

The method provided by the present invention uses a molecular sieve in a water separator to absorb a small amount of water generated in the late stage of azeotropic water separation of the condensation reaction, thereby promoting the reaction to proceed completely. Compared with other disclosed methods, this method has the advantages of: less dehydrating agent is used, does not enter the reaction system, is easy to separate, and is simple to operate.

The method for preparing atracurium besylate by using refined 1,5-pentanediol and benzenesulfonic acid monohydrate provided by the present invention avoids the impurities in commercially available pentanediol from participating in the reaction, avoids the generation of impurities that are difficult to remove, greatly simplifies the purification steps, avoids the use and consumption of a large amount of solvents in the purification link, stabilizes the product quality, and significantly improves the total yield and product purity.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 is a HPLC spectrum of the reaction solution in Example 1;

Fig. 2 is the HPLC spectrum of the product solid I obtained in Example 1;

Fig. 3 is the HPLC spectrum of the reaction solution in Example 2;

FIG4 is an HPLC spectrum of the solid product I obtained in Example 2;

FIG5 is a GC detection spectrum of crude 1,5-pentanediol before purification and refined 1,5-pentanediol after purification in Example 3;

FIG6 is a GC detection spectrum of purified 1,5-pentanediol after purification in Example 3;

FIG. 7 is an HPLC spectrum of the product solid I obtained in Example 4.

Detailed ways

The following examples illustrate embodiments of the present invention. However, it should be understood that embodiments of the present invention are not limited to the specific details in the following examples, as other variations are known and obvious to those of ordinary skill in the art in view of the disclosure of the present invention. The refined 1,5-pentanediol used in the examples was prepared by Example 3.

Embodiment 1:

Compound II (10 g, 17.0 mmol, 1 eq), refined 1,5-pentanediol (0.842 g, 8.1 mmol, 0.475 eq, GC purity 99.8%, single impurity less than 0.10%), benzenesulfonic acid monohydrate (6.29 g, 35.7 mmol) were added to dichloromethane (150 ml), heated to reflux and separate water for 5-6 hours, 4A spherical molecular sieves (10 g) were added to the water separator, reflux and separate water for 15 hours, HPLC detection (reaction liquid purity 93%), heating was stopped, cooled to room temperature, and washed with water 4 times (50 ml*4), after layering, the dichloromethane layer was concentrated to a small volume under reduced pressure, added dropwise to toluene (50 ml), stirred, filtered, and dried to obtain solid compound I (9 g), with a molar yield of about 89% (calculated based on the yield of complete conversion of refined 1,5-pentanediol), and a product purity of 99.5%.

The HPLC spectrum of the reaction liquid is shown in Figure 1. The HPLC spectrum of the solid is shown in Figure 2.

Embodiment 2:

Compound II (10 g, 17.0 mmol, 1 eq), commercially available 1,5-pentanediol (0.842 g, 8.1 mmol, 0.475 eq), and benzenesulfonic acid monohydrate (6.29 g, 35.7 mmol) were added to dichloromethane (150 ml), and the mixture was heated to reflux and separated for 5 hours. 4A spherical molecular sieves (10 g) were added to the water separator, and reflux and separated for 15 hours. HPLC detection (reaction liquid purity 88%) was performed, and the heating was stopped. After cooling to room temperature, water was added and washed 4 times (50 ml*4). After stratification, the dichloromethane layer was concentrated under reduced pressure to a small volume, added to toluene (50 ml), stirred, and filtered to obtain compound I (9 g) with a molar yield of 90% and a product purity of 94.3%.

The HPLC spectrum of the reaction liquid is shown in Figure 3. The HPLC purity of the solid is shown in Figure 4.

Embodiment 3:

Commercially available crude 1,5-pentanediol (0.5 eq) and p-nitrobenzoic acid (1 eq) are added to toluene, refluxed and separated under the catalysis of benzenesulfonic acid (5%). After the reaction is completed, the heating is stopped, the solid is slowly cooled and crystallized, filtered, and the solid is added to THF and sodium hydroxide and aqueous solution and heated for hydrolysis. After the reaction is completed, the pH is adjusted to 3-4 with concentrated sulfuric acid, the solid is filtered, the filtrate is concentrated to a small volume and THF is added for pulping, the salt is filtered, the filtrate is concentrated under reduced pressure to concentrate the water to dryness, and then the product is evaporated, with a yield of 70-80% and a GC purity of 99.88%.

The GC detection spectra of crude 1,5-pentanediol before purification and refined 1,5-pentanediol after purification are shown in FIG5 .

The GC detection spectrum of purified 1,5-pentanediol is shown in Figure 6.

Embodiment 4:

Compound II (10 g, 17.0 mmol, 1 eq), refined 1,5-pentanediol (0.842 g, 8.1 mmol, 0.475 eq), and benzenesulfonic acid monohydrate (6.29 g, 35.7 mmol) were added to toluene (150 ml), heated to reflux and separate water for 5 hours, anhydrous sodium sulfate (10 g) was added to the water separator, and reflux and separate water for 15 hours. After HPLC detection, the heating was stopped, and after cooling to room temperature, water was added and washed 4 times (50 ml*4). After layering, the dichloromethane layer was concentrated to a small volume under reduced pressure, methyl tert-butyl ether was added dropwise, stirred, a solid was precipitated, filtered, and dried to obtain solid compound I (9 g) with a molar yield of about 89% and a product purity of 98.7%.

The solid HPLC spectrum is shown in Figure 7.

Embodiment 5:

Compound II (10 g, 17.0 mmol, 1 eq), commercially available 1,5-pentanediol (0.842 g, 8.1 mmol, 0.475 eq), and benzenesulfonic acid monohydrate (6.29 g, 35.7 mmol) were added to toluene (150 ml), heated to reflux and separate water for 5 hours, anhydrous sodium sulfate (10 g) was added to the water separator, and reflux and separate water for 15 hours. After HPLC detection, the heating was stopped, and after cooling to room temperature, water was added and washed 4 times (50 ml*4). After stratification, the dichloromethane layer was concentrated to a small volume under reduced pressure, and cyclohexanone (50 ml) was added dropwise, stirred, and a solid was precipitated. The solid was filtered and dried to obtain a solid compound I (9 g) with a molar yield of about 90% and a product purity of 95.7%.

Embodiment 6:

Compound II (10 g, 17.0 mmol, 1 eq), commercially available 1,5-pentanediol (0.842 g, 8.1 mmol, 0.475 eq), and benzenesulfonic acid monohydrate (6.29 g, 35.7 mmol) were added to ethyl acetate (150 ml), heated to reflux and separate water for 5 hours, anhydrous calcium chloride (10 g) was added to the water separator, and reflux and separate water for 15 hours. After HPLC detection, the heating was stopped, and after cooling to room temperature, water was added and washed 4 times (50 ml*4). After stratification, the dichloromethane layer was concentrated to a small volume under reduced pressure, and n-hexane (50 ml) was added dropwise, stirred, and a solid was precipitated. It was filtered and dried to obtain a solid compound I (9 g) with a molar yield of about 90% and a product purity of 91.8%.

The above examples are for illustrative purposes only, and the scope of the present invention is not limited thereby. Modifications will be apparent to those skilled in the art, and the present invention is limited only by the scope of the appended claims.

Claims (8)

1. A method for preparing atracurium besylate represented by structural formula I, characterized in that: The method comprises the following steps: The compound represented by formula II, the refined 1,5-pentanediol represented by formula III, and the catalyst benzenesulfonic acid monohydrate represented by formula IV are dissolved in an organic solvent to cause a condensation reaction to obtain atracurium benzenesulfonate represented by formula I; Wherein, the refined 1,5-pentanediol is prepared by a preparation method comprising the following steps: Crude 1,5-pentanediol of structural formula III and p-nitrobenzoic acid of structural formula V undergo condensation reaction under acid catalysis to obtain a compound of formula VI, and then undergo hydrolysis reaction under alkaline conditions to obtain refined 1,5-pentanediol; wherein the acid is selected from one or more of benzenesulfonic acid, methanesulfonic acid, and sulfuric acid. 2. The preparation method according to claim 1, characterized in that the organic solvent is selected from one or a mixture of dichloromethane, chlorobenzene, toluene, xylene, ethyl acetate, methyl acetate, propyl acetate, butyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, acetonitrile, acetone or butanone. 3. The preparation method according to claim 1 is characterized in that the reaction temperature of the condensation reaction is 30-160 degrees Celsius, and a desiccant is added to the reaction mixture or the reflux water separation device. 4. The preparation method according to claim 2, characterized in that: the organic solvent is dichloromethane, and the reaction temperature of the condensation reaction is the reflux temperature of dichloromethane. 5. The preparation method according to claim 3, characterized in that the reactor where the condensation reaction occurs is equipped with a reflux water separation device, and one or more of molecular sieves, sodium sulfate, magnesium sulfate, calcium chloride, and silica gel are added to the reflux water separation device as a desiccant. 6. The preparation method according to claim 1 is characterized in that: the alkaline condition is in the presence of one or more of sodium hydroxide, sodium hydroxide, potassium carbonate, and sodium carbonate. 7. A method for preparing refined 1,5-pentanediol, comprising the following steps: Crude 1,5-pentanediol of structural formula III and p-nitrobenzoic acid of structural formula V are subjected to a condensation reaction under acid catalysis to obtain a compound of formula VI, and then a hydrolysis reaction is carried out under alkaline conditions to obtain refined 1,5-pentanediol; Wherein, the acid is selected from one or more of benzenesulfonic acid, methanesulfonic acid and sulfuric acid. 8. The preparation method according to claim 7, characterized in that: the alkaline condition is in the presence of one or more of sodium hydroxide, sodium hydroxide, potassium carbonate, and sodium carbonate.