CN112047883A - Preparation method of cisatracurium besylate - Google Patents

Preparation method of cisatracurium besylate Download PDF

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CN112047883A
CN112047883A CN201910491476.2A CN201910491476A CN112047883A CN 112047883 A CN112047883 A CN 112047883A CN 201910491476 A CN201910491476 A CN 201910491476A CN 112047883 A CN112047883 A CN 112047883A
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pentanediol
reaction
acid
condensation reaction
formula
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CN112047883B (en
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沈敬山
朱富强
吴明军
蒋德辉
蒋翔锐
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Shanghai Institute of Materia Medica of CAS
Topharman Shanghai Co Ltd
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Topharman Shanghai Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/18—Aralkyl radicals
    • C07D217/20—Aralkyl radicals with oxygen atoms directly attached to the aromatic ring of said aralkyl radical, e.g. papaverine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/74—Separation; Purification; Use of additives, e.g. for stabilisation
    • C07C29/88—Separation; Purification; Use of additives, e.g. for stabilisation by treatment giving rise to a chemical modification of at least one compound
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids

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Abstract

The invention belongs to the field of pharmaceutical chemistry and chemical synthesis, and particularly relates to a preparation method and application of atracurium. The invention provides a synthesis method of high-purity cisatracurium besylate. The invention also provides a preparation method for the raw material used for synthesizing the high-purity atracurium for refining the 1, 5-pentanediol with high purity. The method for synthesizing cisatracurium besylate has the following advantages: the method is simple and convenient, has high yield, high conversion rate of raw materials and high product purity, and is already used for industrial production.

Description

Preparation method of cisatracurium besylate
Technical Field
The invention belongs to the field of pharmaceutical chemistry and chemical synthesis, and particularly relates to cisatracurium besylate, and a preparation method and application thereof.
Background
Cisatracurium besilate has no obvious histamine release, small muscle relaxation effect, no accumulation effect, small cardiovascular reaction and small dependence on the functions of liver, kidney and other organs, and is an ideal medium-aging non-depolarizing muscle relaxant.
Various methods for synthesizing cisatracurium besilate have been reported in public. WO9200965 reports that R-tetrahydropapaverine and pentanediol diacrylate are subjected to addition reaction, then are dissociated, and further react with methyl benzenesulfonate to obtain atracurium benzenesulfonate, and finally, column chromatography resolution is carried out to obtain cis-atracurium benzenesulfonate.
Figure BDA0002087184890000011
WO2009007946 discloses another synthesis method, in which a monoamine propionic acid tert-butyl ester reacts with methyl benzenesulfonate to generate monoamine propionic acid tert-butyl ester quaternary ammonium salt, the obtained monoamine propionic acid tert-butyl ester quaternary ammonium salt is then split to obtain cis-monoamine propionic acid tert-butyl ester quaternary ammonium salt, the obtained cis-monoamine propionic acid quaternary ammonium salt is hydrolyzed to obtain monoamine propionic acid quaternary ammonium salt, the obtained product is continuously reacted with pentanediol to obtain cis-benzenesulphonic acid atracurium salt, the monoamine propionic acid quaternary ammonium salt can also be reacted with pentanediol to obtain cis-monoamine propionic acid pentanediol ester, and finally, the obtained product is condensed with another molecule of monoamine propionic acid quaternary.
Figure BDA0002087184890000021
The raw materials used in the above patents are all commercially available raw materials. The pentanediol, which is currently available on the market and can be used for the preparation of products on an industrial scale, contains a variety of impurities, the main impurities being 1, 6-hexanediol, 1-methylpentanediol, 2-methylpentanediol, 3-methylpentanediol and the like. The impurities with chemical activity can be subjected to condensation reaction with the raw material compound II under the catalysis of benzenesulfonic acid to generate impurities, and the impurities are close to the properties of the product and are not easy to purify.
The synthetic method reported in WO2009007946 has some notable problems. Specifically, the conversion of the condensed monoamine propionic acid quaternary ammonium salt raw material is incomplete, and the rest raw material is not easy to purify; the raw material pentanediol which can be purchased in the market often contains impurities which can participate in the reaction, so that the quality content is high, a qualified product can be obtained only by complex purification steps, and the product quality is unstable; the purification process of various impurities needs to consume a large amount of solvent, which causes pollution. The above problems are more serious in industrial production.
Therefore, it is very important to develop a new method for preparing high-purity cis-atracurium besylate with high conversion rate, and a method for refining raw material pentanediol needs to be developed, and the new method needs to meet the requirements of an ESH management system and conforms to higher pursuit and concept of safe, environment-friendly and green synthesis.
Object of the Invention
In order to overcome the defects in the prior art, the invention belongs to the field of pharmaceutical chemistry and chemical synthesis, and particularly relates to a preparation method of cisatracurium besylate.
Technical scheme
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:
Figure BDA0002087184890000031
the method comprises the following steps:
dissolving the purified 1, 5-pentanediol shown as the formula III, the compound shown as the formula II and the benzenesulfonic acid monohydrate shown as the catalyst shown as the formula IV in an organic solvent, and carrying out condensation reaction to obtain the cis-benzenesulfonic acid atracurium shown as the formula I.
Preferably, the organic solvent used in the condensation reaction is selected from one or more 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 ℃, and further preferably, a drying agent is added into 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 trap, into which a mixture of one or more of molecular sieves, sodium sulfate, magnesium sulfate, calcium chloride, silica gel is added as a drying agent.
And after the reaction is finished, cooling to room temperature, washing away benzenesulfonic acid and water-soluble impurities by using water, concentrating a dichloromethane layer under reduced pressure to a small volume, dropwise adding the dichloromethane layer into an organic solvent, separating out a solid, filtering, and drying to obtain the high-purity cis-benzenesulfonic acid atracurium.
The organic solvent used in the purification process is one or a mixture of more of toluene, cyclohexane, xylene, chlorobenzene, n-hexane, petroleum ether, n-heptane, methyl tert-butyl ether, isopropyl ether, n-butyl ether, diethyl ether, tetrahydrofuran, methyl tetrahydrofuran, ethyl acetate, methyl formate, ethyl formate, methyl acetate, isopropyl acetate, tert-butyl acetate, ethyl propionate, methyl benzoate, chlorobutane, chloropentane, chlorocyclopentane, chlorohexane, chlorocyclohexane, acetone, butanone, pentanone, cyclohexanone, and the like.
Another object of the present invention is to provide the method for preparing purified 1, 5-pentanediol, comprising the steps of:
Figure BDA0002087184890000032
the crude 1, 5-pentanediol with the structural formula III and the p-nitrobenzoic acid with the structural formula V are subjected to condensation reaction under the catalysis of acid to obtain a compound with the structural formula VI, and then hydrolysis reaction is carried out under the alkaline condition to obtain the refined 1, 5-pentanediol.
Preferably, the acid is selected from one or more of benzenesulfonic acid, methanesulfonic acid, sulfuric acid, and the like
Preferably, the alkaline conditions are in the presence of one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate.
The purity of the purified 1, 5-pentanediol reaches up to 99.8 percent, the content of a single impurity is controlled to be below 0.06 percent, and the generation of the impurity is effectively controlled from the source.
Advantageous effects
According to the method provided by the invention, a small amount of moisture generated is absorbed in the water separator by using the molecular sieve at the later stage of azeotropic water separation of the condensation reaction, so that the reaction is promoted to be completely carried out. Compared with other disclosed methods, the method has the advantages that: the dosage of the dehydrating agent is less, the dehydrating agent does not enter a reaction system, the separation is easy, and the operation is simple and convenient.
The method for preparing the cisatracurium besylate by using the refined 1, 5-pentanediol and the benzenesulfonic acid monohydrate, provided by the invention, avoids the participation of impurities in commercially available pentanediol in reaction and the generation of impurities which are difficult to remove, greatly simplifies the purification steps, avoids the use and consumption of a large amount of solvents in the purification link, and has the advantages of stable product quality and obviously improved total yield and product purity.
Drawings
FIG. 1 is an HPLC chromatogram of the reaction solution in example 1;
FIG. 2 is an HPLC chromatogram of the product solid I obtained in example 1;
FIG. 3 is an HPLC chromatogram of the reaction solution in example 2;
FIG. 4 is an HPLC chromatogram of the product solid I obtained in example 2;
FIG. 5 is a GC analysis of crude 1, 5-pentanediol before purification and refined 1, 5-pentanediol after purification in example 3;
FIG. 6 is a GC detection spectrum of purified 1, 5-pentanediol obtained in example 3;
FIG. 7 is an HPLC chromatogram of product solid I obtained in example 4.
Detailed Description
Embodiments of the present invention are illustrated by the following examples. However, it is to be understood that embodiments of the invention are not limited to the specific details of the following examples, since other variations will be apparent to those of ordinary skill in the art in view of the present disclosure. The purified 1, 5-pentanediol used in the examples was prepared from example 3.
Example 1:
adding compound II (10g, 17.0mmol, 1eq), purified 1, 5-pentanediol (0.842g, 8.1mmol, 0.475eq, GC purity 99.8%, single impurities less than 0.10%), benzenesulfonic acid monohydrate (6.29g, 35.7mmol) into dichloromethane (150ml), heating under reflux for 5-6 hours, adding 4A spherical molecular sieve (10g) into a water separator, continuing refluxing for water separation for 15 hours, detecting by HPLC (detection by HPLC (reaction liquid purity 93%), stopping heating, cooling to room temperature, adding water for 4 times (50ml 4), concentrating the dichloromethane layer to a small volume under reduced pressure after separation, dropwise adding the dichloromethane layer into toluene (50ml), stirring, filtering, and drying to obtain solid compound I (9g), wherein the molar yield is about 89% (calculated on the yield of complete conversion of the purified 1, 5-pentanediol), and the product purity is 99.5%.
The HPLC chromatogram of the reaction solution is shown in FIG. 1. The HPLC profile of the solid is shown in FIG. 2.
Example 2:
adding compound II (10g, 17.0mmol, 1eq), commercial 1, 5-pentanediol (0.842g, 8.1mmol, 0.475eq), benzenesulfonic acid monohydrate (6.29g, 35.7mmol) into dichloromethane (150ml), heating under reflux for 5 hours, adding 4A spherical molecular sieve (10g) into a water separator, continuing to reflux for 15 hours, performing HPLC (purity of the reaction solution is 88%), stopping heating, cooling to room temperature, adding water for washing 4 times (50 ml. 4), concentrating the dichloromethane layer to a small volume under reduced pressure after separation, adding the dichloromethane layer into toluene (50ml), stirring, and filtering to obtain compound I (9g), wherein the molar yield is 90% and the product purity is 94.3%.
The HPLC chromatogram of the reaction solution is shown in FIG. 3. The solid HPLC purity is shown in fig. 4.
Example 3:
Figure BDA0002087184890000051
adding commercial crude 1, 5-pentanediol (0.5eq) and p-nitrobenzoic acid (1eq) into toluene, refluxing and water splitting under the catalysis of benzenesulfonic acid (5%), stopping heating after the reaction is finished, slowly cooling and crystallizing the solid, filtering, adding the solid into THF, sodium hydroxide and an aqueous solution, heating for hydrolysis, adjusting the pH to 3-4 by concentrated sulfuric acid after the reaction is finished, filtering the solid, concentrating the filtrate to a small volume, adding THF for pulping, filtering the salt, concentrating the filtrate under reduced pressure to dry the water, evaporating the product, wherein the yield is 70-80%, and the GC purity is 99.88%.
GC detection spectra of the crude 1, 5-pentanediol before purification and the purified 1, 5-pentanediol after purification are shown in FIG. 5.
The GC detection spectrum of the purified 1, 5-pentanediol is shown in FIG. 6.
Example 4:
adding compound II (10g, 17.0mmol, 1eq), refined 1, 5-pentanediol (0.842g, 8.1mmol, 0.475eq), benzenesulfonic acid monohydrate (6.29g, 35.7mmol) into toluene (150ml), heating under reflux for 5 hours, adding anhydrous sodium sulfate (10g) into a water separator, continuing to reflux for 15 hours, stopping heating after HPLC detection reaction is finished, cooling to room temperature, adding water for 4 times (50ml 4), concentrating a dichloromethane layer to a small volume under reduced pressure after layering, dropwise adding methyl tert-butyl ether, stirring, precipitating a solid, filtering, and drying to obtain solid compound I (9g), wherein the molar yield is about 89%, and the purity of the product is 98.7%.
The solid HPLC spectrum is shown in FIG. 7.
Example 5:
adding compound II (10g, 17.0mmol, 1eq), commercial 1, 5-pentanediol (0.842g, 8.1mmol, 0.475eq), benzenesulfonic acid monohydrate (6.29g, 35.7mmol) into toluene (150ml), heating under reflux for 5 hours, adding anhydrous sodium sulfate (10g) into a water separator, continuing to reflux for 15 hours, stopping heating after HPLC detection reaction is finished, cooling to room temperature, adding water for 4 times (50ml 4), concentrating a dichloromethane layer to a small volume under reduced pressure after layering, dropwise adding cyclohexanone (50ml), stirring, precipitating a solid, filtering, and drying to obtain a solid compound I (9g), wherein the molar yield is about 90% and the purity of the product is 95.7%.
Example 6:
adding compound II (10g, 17.0mmol, 1eq), commercial 1, 5-pentanediol (0.842g, 8.1mmol, 0.475eq), benzenesulfonic acid monohydrate (6.29g, 35.7mmol) into ethyl acetate (150ml), heating under reflux for 5 hours, adding anhydrous calcium chloride (10g) into a water separator, continuing to reflux for 15 hours, stopping heating after HPLC detection reaction is finished, cooling to room temperature, adding water for 4 times (50 ml. 4), concentrating a dichloromethane layer to a small volume under reduced pressure after separation, dropwise adding n-hexane (50ml), stirring, precipitating a solid, filtering, and drying to obtain a solid compound I (9g), wherein the molar yield is about 90% and the product purity is 91.8%.
The above examples are for illustrative purposes only and the scope of the present invention is not limited thereto. Modifications will be apparent to those skilled in the art and the invention is limited only by the scope of the appended claims.

Claims (8)

1. A method for preparing cisatracurium besylate represented by a structural formula I is characterized by comprising the following steps:
Figure FDA0002087184880000011
the method comprises the following steps:
dissolving the compound shown in the formula II, the purified 1, 5-pentanediol shown in the formula III and the benzenesulfonic acid monohydrate shown in the formula IV serving as a catalyst in an organic solvent, and carrying out condensation reaction to obtain the cisatracurium besylate shown in the formula I.
2. The method of claim 1, wherein: the organic solvent is selected from one or a mixture of more 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 method of claim 1, wherein: the reaction temperature of the condensation reaction is 30-160 ℃, and a drying agent is added into the reaction mixture or the reflux water separation device.
4. The method of claim 2, wherein: the organic solvent is dichloromethane, and the reaction temperature of the condensation reaction is dichloromethane reflux temperature.
5. The production method according to claim 3, characterized in that: a reflux water separation device is assembled on a reactor in which condensation reaction occurs, and one or more of molecular sieve, sodium sulfate, magnesium sulfate, calcium chloride and silica gel are added into the reflux water separation device as a drying agent.
6. The production method according to any one of claims 1 to 5, characterized in that: the preparation method of the refined 1, 5-pentanediol comprises the following steps:
Figure FDA0002087184880000012
the crude 1, 5-pentanediol with the structural formula III and the p-nitrobenzoic acid with the structural formula V are subjected to condensation reaction under the catalysis of acid to obtain a compound with the structural formula VI, and then hydrolysis reaction is carried out under the alkaline condition to obtain the refined 1, 5-pentanediol.
7. The method of claim 6, wherein: the acid is selected from one or more of benzene sulfonic acid, methane sulfonic acid and sulfuric acid.
8. The method of claim 6, wherein: preferably, the alkaline conditions are in the presence of one or more of sodium hydroxide, potassium carbonate, sodium carbonate.
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112778200A (en) * 2021-01-20 2021-05-11 江苏诚信药业有限公司 Preparation method and application of cisatracurium besilate
CN113372271A (en) * 2020-12-24 2021-09-10 上海药坦药物研究开发有限公司 Preparation method of cisatracurium besylate
CN115947685A (en) * 2023-02-07 2023-04-11 山东铂源药业股份有限公司 Preparation method of cisatracurium besilate chiral isomer impurity

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3010510A1 (en) * 1979-03-23 1980-10-02 Basf Wyandotte Corp Purifying diol by treatment with sulphonic acid - for prodn. of polyester poly:ol(s) etc. of better colour
JP2004238340A (en) * 2003-02-07 2004-08-26 Idemitsu Petrochem Co Ltd High-purity alkane-1,2-diol and method for producing the same
US20040225161A1 (en) * 2003-05-06 2004-11-11 Sunkara Hari Babu Hydrogenation of chemically derived 1,3-propanediol
WO2009007946A1 (en) * 2007-07-09 2009-01-15 Chemagis Ltd. Process for producing cisatracurium and associated intermediates

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3010510A1 (en) * 1979-03-23 1980-10-02 Basf Wyandotte Corp Purifying diol by treatment with sulphonic acid - for prodn. of polyester poly:ol(s) etc. of better colour
JP2004238340A (en) * 2003-02-07 2004-08-26 Idemitsu Petrochem Co Ltd High-purity alkane-1,2-diol and method for producing the same
US20040225161A1 (en) * 2003-05-06 2004-11-11 Sunkara Hari Babu Hydrogenation of chemically derived 1,3-propanediol
WO2009007946A1 (en) * 2007-07-09 2009-01-15 Chemagis Ltd. Process for producing cisatracurium and associated intermediates

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113372271A (en) * 2020-12-24 2021-09-10 上海药坦药物研究开发有限公司 Preparation method of cisatracurium besylate
CN112778200A (en) * 2021-01-20 2021-05-11 江苏诚信药业有限公司 Preparation method and application of cisatracurium besilate
CN115947685A (en) * 2023-02-07 2023-04-11 山东铂源药业股份有限公司 Preparation method of cisatracurium besilate chiral isomer impurity

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