CN112047883B - Preparation method of atracurium cis-besylate - Google Patents

Preparation method of atracurium cis-besylate Download PDF

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CN112047883B
CN112047883B CN201910491476.2A CN201910491476A CN112047883B CN 112047883 B CN112047883 B CN 112047883B CN 201910491476 A CN201910491476 A CN 201910491476A CN 112047883 B CN112047883 B CN 112047883B
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pentanediol
acid
reaction
preparation
structural formula
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CN112047883A (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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Shanghai Institute of Materia Medica of CAS
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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

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 cis-besylate
Technical Field
The invention belongs to the fields of pharmaceutical chemistry and chemical synthesis, and in particular relates to atracurium cis-besylate, a preparation method and application thereof.
Background
The cisatracurium besylate has no obvious histamine release, small muscle relaxation effect, no accumulation effect, small cardiovascular response, and small dependence on functions of organs such as liver, kidney and the like, and is an ideal medium-aging non-depolarizing muscle relaxant.
Various synthetic methods of cisatracurium besylate have been reported. WO9200965 reports that R-tetrahydropapaverine undergoes an addition reaction with pentanediol diacrylate, then is free, further reacts with methyl benzenesulfonate to give atracurium besylate, and finally is resolved by column chromatography to give atracurium besylate in cis form.
WO2009007946 discloses another synthesis method, in which tertiary butyl monoamine propionate is reacted with methyl benzenesulfonate to produce tertiary butyl monoamine propionate quaternary ammonium salt, then the tertiary butyl monoamine propionate quaternary ammonium salt is resolved to obtain cis-tertiary butyl monoamine propionate quaternary ammonium salt, then the cis-tertiary butyl monoamine propionate quaternary ammonium salt is hydrolyzed to obtain cis-atracurium besylate, and the cis-atracurium besylate is further reacted with pentanediol to obtain cis-atracurium besylate, or the cis-atracurium besylate is finally condensed with another molecule of monoaminopropionic acid quaternary ammonium salt.
The raw materials used in the above patents are all commercially available raw materials. Pentanediol, which is currently available on the market and can be used for preparing products on an industrial scale, contains various impurities, and the main impurities are 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 products and are not easy to purify.
The synthetic method reported in WO2009007946 has some notable problems. Specifically, the condensed monoamine propionic acid quaternary ammonium salt raw material is not completely converted, and the rest raw materials are 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 higher, a qualified product can be obtained only through complicated purification steps, and the product quality is unstable; the purification process of various impurities requires a large amount of solvent, and causes pollution. The above problems are highlighted in greater severity in industrial production.
Therefore, development of a new method for preparing high-purity cis-atracurium besylate with high conversion rate is particularly important, and a method for refining raw material pentanediol is also required, and the new method is required to meet the requirements of an ESH management system and meet the higher pursuit and concept of safe, environment-friendly and green synthesis.
Object of the Invention
The invention belongs to the fields of pharmaceutical chemistry and chemical synthesis, and particularly relates to a preparation method of cis-atracurium besilate.
Technical proposal
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 scheme:
The method comprises the following steps:
dissolving refined 1, 5-pentanediol shown in a formula III, a compound shown in a formula II and catalyst benzenesulfonic acid monohydrate shown in a formula IV in an organic solvent to perform condensation reaction to obtain atracurium cis-benzenesulfonate shown in a 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 condensation reaction has a reaction temperature of 30-160 degrees celsius, and more preferably, a desiccant is added to the reaction mixture or the reflux water splitting device.
More preferably, the organic solvent used is methylene chloride; more preferably, the reaction temperature of the condensation reaction is the reflux temperature of methylene chloride. More preferably, the reactor is equipped with a reflux water separator to which a mixture of one or more of molecular sieve, sodium sulfate, magnesium sulfate, calcium chloride, silica gel is added as a desiccant.
After the reaction is finished, cooling to room temperature, washing off benzenesulfonic acid and water-soluble impurities with water, concentrating a dichloromethane layer to a small volume under reduced pressure, dripping the dichloromethane layer into an organic solvent to precipitate solid, filtering, and drying to obtain high-purity cis-atracurium besilate.
The organic solvent used in the above purification process is selected from one or 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, etc.
Another object of the present invention is to provide a process for producing the purified 1, 5-pentanediol, comprising the steps of:
the crude 1, 5-pentanediol with the structural formula III and 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 alkaline conditions to obtain the 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 in the presence of one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate.
The purity of the purified 1, 5-pentanediol is up to 99.8%, the content of single impurities is controlled below 0.06%, and the generation of the impurities is effectively controlled from the source.
Advantageous effects
In the method provided by the invention, a molecular sieve is used for absorbing a small amount of water generated in a water separator in the later stage of condensation reaction azeotropic water separation, so that the reaction is promoted to be completely carried out. The advantages of this approach over other disclosed approaches are: the dosage of the dehydrating agent is small, the dehydrating agent does not enter the reaction system, the dehydrating agent is easy to separate, and the operation is simple and convenient.
The method for preparing the atracurium cis-besylate by using refined 1, 5-pentanediol and benzene sulfonic acid monohydrate provided by the invention avoids the participation of impurities in the commercial pentanediol in the reaction, avoids 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, has stable product quality, and obviously improves the total yield and the product purity.
Drawings
FIG. 1 is an HPLC chart of the reaction solution in example 1;
FIG. 2 is an HPLC chart of the product solid I obtained in example 1;
FIG. 3 is an HPLC chart of the reaction solution in example 2;
FIG. 4 is an HPLC chart of the product solid I obtained in example 2;
FIG. 5 is a GC analysis chart of crude 1, 5-pentanediol before purification and refined 1, 5-pentanediol after purification in example 3;
FIG. 6 is a GC analysis chart of purified 1, 5-pentanediol obtained in example 3;
FIG. 7 is an HPLC chart of product solid I obtained in example 4.
Detailed Description
Embodiments of the present invention are illustrated by the following examples. It is to be understood, however, that the embodiments of the invention are not limited to the specific details set forth in the following examples, as other variations will be known and apparent to those of ordinary skill in the art in light of the present disclosure. The refined 1, 5-pentanediol used in the examples was prepared from example 3.
Example 1:
Compound II (10 g,17.0mmol,1 eq), refined 1, 5-pentanediol (0.842 g,8.1mmol,0.475eq, GC purity 99.8%, single impurities less than 0.10%), benzenesulfonic acid monohydrate (6.29 g,35.7 mmol) were added to dichloromethane (150 ml), heated to reflux for 5-6 hours, 4A ball molecular sieve (10 g) was added to the water separator, reflux was continued for 15 hours, HPLC detection (purity of reaction solution 93%), heating was stopped, cooled to room temperature, water was added to wash 4 times (50 ml. Times.4), after separation, the dichloromethane layer was concentrated to a small volume under reduced pressure, toluene (50 ml) was added dropwise, stirred, filtered, and dried to give solid compound I (9 g), molar yield about 89% (calculated as yield of complete conversion of refined 1, 5-pentanediol), product purity 99.5%.
The HPLC chart of the reaction solution is shown in FIG. 1. The solid HPLC profile is shown in figure 2.
Example 2:
Compound II (10 g,17.0mmol,1 eq), commercially available 1, 5-pentanediol (0.842 g,8.1mmol, 0.475eq), benzenesulfonic acid monohydrate (6.29 g,35.7 mmol) was added to dichloromethane (150 ml), heated to reflux and split water for 5 hours, 4A spherical molecular sieve (10 g) was added to the splitter, water splitting was continued for 15 hours, HPLC detection (reaction purity 88%), heating was stopped, cooling to room temperature, water washing was added 4 times (50 ml of 4), after delamination, the dichloromethane layer was concentrated to a small volume under reduced pressure, added to toluene (50 ml), stirred, filtered to give compound I (9 g), molar yield 90%, product purity 94.3%.
The HPLC profile of the reaction solution is shown in FIG. 3. The solid HPLC purity is shown in fig. 4.
Example 3:
Commercial crude 1, 5-pentanediol (0.5 eq) and p-nitrobenzoic acid (1 eq) are added into toluene, water is refluxed and separated under the catalysis of benzenesulfonic acid (5%), after the reaction is finished, heating is stopped, the solid is slowly cooled and crystallized, filtered, the solid is added into THF, sodium hydroxide and aqueous solution for heating and hydrolyzing, after the reaction is finished, concentrated sulfuric acid is used for regulating pH to 3-4, the solid is filtered, the filtrate is concentrated to a small volume, THF is added for pulping, salt is filtered, the filtrate is concentrated under reduced pressure to be concentrated to be dry, and then the product is distilled out, and the yield is 70-80% and the GC purity is 99.88%.
The GC analysis of the purified 1, 5-pentanediol and the purified 1, 5-pentanediol before purification is shown in FIG. 5.
The GC detection spectrum of the purified 1, 5-pentanediol is shown in FIG. 6.
Example 4:
compound II (10 g,17.0mmol,1 eq), refined 1, 5-pentanediol (0.842 g,8.1mmol, 0.475eq), benzenesulfonic acid monohydrate (6.29 g,35.7 mmol) was added to toluene (150 ml), heated to reflux and split water for 5 hours, anhydrous sodium sulfate (10 g) was added to a water splitter, water splitting was continued for 15 hours under reflux, after HPLC detection reaction was completed, heating was stopped, cooled to room temperature, water was added to wash 4 times (50 ml of 4), after delamination, the dichloromethane layer was concentrated to a small volume under reduced pressure, methyl tert-butyl ether was added dropwise, stirred, precipitated solid, filtered, and dried to give solid compound I (9 g), molar yield of about 89%, product purity 98.7%.
The solid HPLC profile is shown in fig. 7.
Example 5:
Compound II (10 g,17.0mmol,1 eq), commercially available 1, 5-pentanediol (0.842 g,8.1mmol, 0.475eq), benzenesulfonic acid monohydrate (6.29 g,35.7 mmol) was added to toluene (150 ml), heated to reflux and split water for 5 hours, anhydrous sodium sulfate (10 g) was added to a water splitter, water splitting was continued for 15 hours under reflux, after completion of the HPLC detection reaction, heating was stopped, cooled to room temperature, water was added to wash 4 times (50 ml of 4), after delamination, the dichloromethane layer was concentrated under reduced pressure to a small volume, cyclohexanone (50 ml) was added dropwise, stirred, precipitated solid, filtered, and dried to give solid compound I (9 g), the molar yield was about 90%, and the product purity was 95.7%.
Example 6:
Compound II (10 g,17.0mmol,1 eq), commercially available 1, 5-pentanediol (0.842 g,8.1mmol, 0.475eq), benzenesulfonic acid monohydrate (6.29 g,35.7 mmol) was added to ethyl acetate (150 ml), heated to reflux and water separated for 5 hours, anhydrous calcium chloride (10 g) was added to the water separator, water was continuously separated by reflux for 15 hours, after the reaction was detected by HPLC, heating was stopped, cooled to room temperature, water was added to wash 4 times (50 ml of 4), after the separation, the dichloromethane layer was concentrated to a small volume under reduced pressure, n-hexane (50 ml) was added dropwise, and the mixture was stirred to precipitate a solid, filtered and dried to give a solid compound I (9 g) with a molar yield of about 90% and a product purity of 91.8%.
The foregoing examples are for illustrative purposes only, and the scope of the present invention is not limited thereto. Modifications will be obvious to those skilled in the art and the present invention is limited only by the scope of the appended claims.

Claims (8)

1. A preparation method of atracurium cis-besylate represented by a structural formula I is characterized by comprising the following steps:
The method comprises the following steps:
Dissolving a compound shown in a formula II, refined 1, 5-pentanediol shown in a formula III and catalyst benzenesulfonic acid monohydrate shown in a formula IV in an organic solvent to perform condensation reaction to obtain cis-atracurium besylate shown in a formula I;
Wherein, the refined 1, 5-pentanediol is prepared by a preparation method comprising the following steps:
The crude 1, 5-pentanediol with the structural formula III and 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 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 method of manufacturing according to claim 1, characterized in that: 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 manufacturing according to claim 1, characterized in that: the reaction temperature of the condensation reaction is 30-160 ℃, and a desiccant is added in the form of a reaction mixture or a reflux water diversion 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 the dichloromethane.
5. A method of preparation according to claim 3, characterized in that: the reactor for condensation reaction is equipped with a reflux water diversion device, and one or more of molecular sieve, sodium sulfate, magnesium sulfate, calcium chloride and silica gel are added into the reflux water diversion device to be used as drying agent.
6. The method of manufacturing according to claim 1, characterized in that: the alkaline condition is in the presence of one or more of sodium hydroxide, potassium carbonate and sodium carbonate.
7. A preparation method of refined 1, 5-pentanediol comprises the following steps:
the crude 1, 5-pentanediol with the structural formula III and 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 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 method of manufacturing according to claim 7, wherein: the alkaline condition is in the presence of one or more of sodium hydroxide, potassium carbonate and sodium carbonate.
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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
CN112778200B (en) * 2021-01-20 2022-09-23 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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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
WO2009007946A1 (en) * 2007-07-09 2009-01-15 Chemagis Ltd. Process for producing cisatracurium and associated intermediates

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US7084311B2 (en) * 2003-05-06 2006-08-01 E. I. Du Pont De Nemours And Company Hydrogenation of chemically derived 1,3-propanediol

Patent Citations (3)

* 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
WO2009007946A1 (en) * 2007-07-09 2009-01-15 Chemagis Ltd. Process for producing cisatracurium and associated intermediates

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