Preparation method of cisatracurium besylate impurities and intermediates thereof

Abstract

The present invention provides a preparation method of cisatracurium besylate impurity and its intermediate, wherein the preparation method of the intermediate is to use tetrahydropapaveline hydrochloride as a starting material, and to separate it with N-acetyl-L-leucine salt after being freed to obtain R-tetrahydropapaveline and S-tetrahydropapaveline; R-tetrahydropapaveline and S-tetrahydropapaveline are condensed with tert-butyl acrylate respectively, and the condensation product is salified with oxalic acid, and then further forms a quaternary ammonium salt with methyl benzenesulfonate, and three intermediates are obtained after crystallization: S-cis ester compound, R-cis ester compound and R-trans ester compound. Then after the S-cis ester compound is hydrolyzed, a monoesterification product is first formed with 1,5-pentanediol, and the monoesterification product is esterified with the hydrolyzate of R-cis ester compound and R-trans ester compound respectively, and then impurity S and impurity V are obtained. The compound prepared by the method has a high purity and can be used as an impurity reference substance for quality control of cisatracurium besylate.

Description

Technical Field

[0001] The invention relates to the technical field of drug synthesis, and in particular to a method for preparing a cisatracurium besylate impurity and an intermediate thereof. Background Art

[0002] Cisatracurium besylate is the R-configuration all-cis isomer among the 10 chiral isomers of atracurium besylate, as shown in Formula I. Compared with atracurium besylate, cisatracurium besylate has great advantages, including no obvious histamine release, strong muscle relaxant effect, no accumulation effect, small cardiovascular response, and little dependence on the functions of organs such as liver and kidney, and is a relatively ideal medium-acting non-depolarizing muscle relaxant.

[0003]

[0004] Drugs with a single chiral configuration can have better efficacy than racemic drugs, and can also reduce the dosage and adverse reactions, while reducing the burden of drug metabolism. Based on the above advantages, cisatracurium besylate has become the mainstream of clinical muscle relaxants.

[0005] The quality of APIs is the key and source of drug quality control. Among them, the research and control of impurities is related to the clinical safety of drugs, and thus becomes one of the key links in API quality control. There are 4 chiral centers in the structure of cisatracurium besylate, with a total of 10 chiral isomers. Theoretically, except for the R all-cis configuration (i.e. cisatracurium besylate), the other 9 are potential impurities.

[0006] The European Pharmacopoeia 10.0 edition lists 22 impurities of cisatracurium besylate that need to be controlled, of which 6 are chiral isomers, namely G, H, S, T, U, and V. Among them, G and H belong to the 1R-1'R configuration, and S, T, U, and V belong to the 1R, 1'S configuration. (The 3 impurity structures not listed are all 1S, 1'S configurations. From the analysis of the process route, the probability of generating these three structures is so low that it can be ignored)

[0007] Wherein the impurity S is 1R-cis-1'S-cis atracurium benzenesulfonate, as shown in Formula II

[0008]

[0009] Impurity V is 1R-trans-1'S-cis-atracurium benzenesulfonate, as shown in Formula III

[0010]

[0011] The impurities currently used in the quality control of cisatracurium besylate are all imported standard products, which are extremely expensive and must be used in each batch, thus greatly increasing the cost to a certain extent. If a suitable preparation method for the above impurities can be developed, it will certainly be of great help to the improvement of economic benefits in large-scale production, and can also further improve the quality control of cisatracurium besylate. Summary of the invention

[0012] In view of the above problems existing in the prior art, the present invention provides a method for preparing cisatracurium besylate impurities and intermediates thereof. The technical solution of the present invention is:

[0013] In a first aspect, the present invention provides a method for preparing an intermediate of cisatracurium besylate impurity S and impurity V, wherein tetrahydropapaverine hydrochloride is used as a starting material, and after being freed, it is separated by using N-acetyl-L-leucine to form a salt to obtain R-tetrahydropapaverine and S-tetrahydropapaverine; R-tetrahydropapaverine and S-tetrahydropapaverine are then condensed with tert-butyl acrylate, and then further formed into a quaternary ammonium salt with methyl benzenesulfonate, and three intermediates are obtained after crystallization: an S-cis ester compound shown in formula IV, an R-cis ester compound shown in formula VI, and an R-trans ester compound shown in formula VII;

[0014]

[0015] The specific reaction equation is:

[0016]

[0017] as well as,

[0018]

[0019] Furthermore, the above preparation method comprises the following steps:

[0020] (a) suspending tetrahydropapaveline hydrochloride in toluene and water, adding sufficient ammonia water, stirring to free, washing, drying and concentrating; then salifying with N-acetyl-L-leucine, filtering to obtain a crude product of S-tetrahydropapaveline-N-acetyl-L-leucine salt, and evaporating the filtrate to obtain a crude product of R-tetrahydropapaveline-N-acetyl-L-leucine salt;

[0021] (b) recrystallizing the crude S-tetrahydropapavine-N-acetyl-L-leucine salt and the crude R-tetrahydropapavine-N-acetyl-L-leucine salt to obtain a refined S-tetrahydropapavine-N-acetyl-L-leucine salt and a refined R-tetrahydropapavine-N-acetyl-L-leucine salt;

[0022] (c) suspending S-tetrahydropapaverine-N-acetyl-L-leucine salt in toluene and water, adding sufficient ammonia water and stirring to make it free, washing, drying and concentrating; then firstly carrying out addition condensation reaction with tert-butyl acrylate, after the reaction is completed, reacting the product with oxalic acid to form oxalate and then purifying; after the oxalate is freed, reacting with methyl benzenesulfonate to form S-quaternary ammonium salt racemate, and refining it three times to obtain S-cis ester compound;

[0023] (e) The reaction process of R-tetrahydropapaverine-N-acetyl-L-leucine salt is the same as step (c) to obtain R-quaternary ammonium salt racemic body, which is purified to obtain R-cis ester compound and R-trans ester compound.

[0024] Furthermore, in the step (a), the molar ratio of tetrahydropapaverine hydrochloride to N-acetyl-L-leucine is 1:(1-1.1).

[0025] Furthermore, the control conditions for the salting and crystallization of the concentrate and N-acetyl-L-leucine in step (a) include: the salting temperature is 80±2°C, the salting and crystallization solvent is anhydrous ethanol, the amount is 8-12 mL / g of the concentrate, and the crystallization temperature is not higher than 15°C.

[0026] Furthermore, the process of recrystallizing the crude S-tetrahydropapaverine-N-acetyl-L-leucine salt in step (b) comprises: dissolving the crude S-tetrahydropapaverine-N-acetyl-L-leucine salt in 8-10 mL / g of anhydrous ethanol at 80±2° C., then lowering the temperature to below 45° C. and stirring for 30-40 minutes, and filtering to obtain a refined S-tetrahydropapaverine-N-acetyl-L-leucine salt.

[0027] Furthermore, the process of recrystallizing the crude R-tetrahydropapavine-N-acetyl-L-leucine salt in step (b) comprises: heating the crude R-tetrahydropapavine-N-acetyl-L-leucine salt with a mixed solvent of acetone and water to dissolve it under reflux, gradually cooling it to below 25° C. and stirring for 3 to 4 hours, and filtering to obtain a refined R-tetrahydropapavine-N-acetyl-L-leucine salt.

[0028] Furthermore, in the acetone and water mixed solvent, the amount of acetone is 26-32 mL / g crude product, preferably 30 mL / g crude product; the amount of water is 0.1-1 mL / g crude product, preferably 0.3 mL / g crude product.

[0029] Preferably, the gradient cooling rate is 10°C / h.

[0030] Furthermore, the control conditions of the addition condensation reaction in step (c) include: the reaction solvent is toluene, the catalyst is glacial acetic acid, the reaction temperature is 60±3° C., and the reaction time is 5 to 7 hours.

[0031] Furthermore, the three refining processes in step (c) include:

[0032] 1) Add dichloromethane to the S-quaternary ammonium salt racemic body and dissolve it at above 32°C, then add methyl tert-butyl ether, and stir and crystallize at 29±2°C. After solid precipitates, continue to keep warm and crystallize for 4h±10min, filter and wash the filter cake with methyl tert-butyl ether, which is the S-trans ester compound;

[0033] 2) The filtrate and washing liquid of step 1) are combined and concentrated to dryness, and dichloromethane is added to dissolve, and then ethyl acetate is added and stirred at 29±1°C for crystallization. After solid precipitation, the mixture is kept warm for crystallization for 3h±10min, and the crude S-cis ester is obtained after filtration;

[0034] 3) Add dichloromethane to the crude S-cis ester and dissolve it at above 32°C, then add ethyl acetate, stir and crystallize at 29±1°C, and continue to keep warm and crystallize for 3h±10min after solid precipitates. Filter the solid and wash it with ethyl acetate, and dry it to obtain S-cis ester, i.e., compound IV.

[0035] Furthermore, the refining process in step (e) comprises:

[0036] (1) adding dichloromethane to the R-quaternary ammonium salt racemic body to dissolve at a temperature above 32° C., then adding methyl tert-butyl ether, and stirring and crystallizing at 29±2° C., and after solid precipitation, continuing to heat and crystallize for 4 h±10 min, filtering and washing the filter cake with methyl tert-butyl ether, and collecting the filter cake and the mixture of the filtrate and the washing liquid respectively;

[0037] (2) dissolving the filter cake in dichloromethane at 37±1° C., adding methyl tert-butyl ether, and cooling the temperature to 22±1° C., stirring for 20±10 min, filtering out the precipitate, and drying to obtain the R-trans ester, i.e., the compound of formula VII;

[0038] (3) The mixture of the filtrate and the washing liquid is concentrated to dryness, and dichloromethane is added to dissolve it. Ethyl acetate is then added and stirred at 29±1°C for crystallization. After solids are precipitated, the mixture is kept warm for crystallization for 3h±10min, and the crude R-cis ester is obtained after filtration;

[0039] (4) Add dichloromethane to the crude R-cis ester and dissolve it at above 32°C, then add ethyl acetate, stir and crystallize at 29±1°C, and keep warm for 3h±10min after solid precipitates. Filter the solid and wash it with ethyl acetate, and dry it to obtain R-cis ester, i.e., compound VI.

[0040] In a second aspect, the present invention provides a method for preparing impurities S and impurities V of cisatracurium besylate, wherein the S-cis ester compound is hydrolyzed and then reacted with 1,5-pentanediol to form a monoesterification product, and the monoesterification product is then esterified with the hydrolyzates of the R-cis ester compound and the R-trans ester compound, respectively, to obtain impurities S and impurity V, and the structural formulas of impurities S and impurity V are:

[0041]

[0042] The specific reaction equation is:

[0043]

[0044] Furthermore, the above preparation method comprises the following steps:

[0045] i) hydrolyzing the S-cis ester in an aqueous benzenesulfonic acid solution at 40±3° C., and reacting the hydrolyzate with 1,5-pentanediol to obtain a monoesterified S-cis ester compound;

[0046] ii) hydrolyzing the R-cis ester compound in an aqueous solution of benzenesulfonic acid at 40±3° C., then adding the S-cis ester monoester compound in toluene and stirring, and refluxing under reduced pressure at 25-35° C. for 24 hours±10 minutes, during which the generated water is continuously separated. After the reaction is completed, washing and drying are performed, and the crude product of impurity S is obtained by dropwise crystallization in methyl tert-butyl ether. The crude product is recrystallized from diethyl ether to obtain a pure product of impurity S of cisatracurium benzylsulfonate;

[0047] iii) The R-trans ester compound is hydrolyzed in an aqueous solution of benzenesulfonic acid at 40±3° C., and then the S-cis ester monoester compound is added and stirred in toluene, and refluxed under reduced pressure at 25-35° C. for 24 hours±10 minutes, during which the generated water is continuously separated. After the reaction is completed, the compound is washed and dried, and then dropped into ether for crystallization to obtain a crude product of impurity V. The crude product is recrystallized from methyl tert-butyl ether to obtain a pure product of cisatracurium benzylsulfonate impurity V.

[0048] The technical solution adopted by the present invention has a safe and reliable synthesis process and good reaction reproducibility, and becomes a method for efficiently preparing cisatracurium besylate impurities S and V. The compound prepared by the method has high purity and can be used as an impurity reference substance for quality control of cisatracurium besylate. BRIEF DESCRIPTION OF THE DRAWINGS

[0049] The drawings described herein are used to provide a further understanding of the present invention and constitute a part of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute an improper limitation of the present invention. In the drawings:

[0050] Figure 1 is the compound of formula VI obtained in Example 4 of the present invention 1 H NMR spectrum.

[0051] Figure 2 is the compound of formula VII obtained in Example 5 of the present invention 1 H NMR spectrum.

[0052] Figure 3 It is the UPLC chromatogram of the compound of formula II (impurity S) obtained in Example 7 of the present invention.

[0053] Figure 4 It is the compound of formula II obtained in Example 7 of the present invention (impurity S) 1 H NMR spectrum.

[0054] Figure 5 It is the UPLC chromatogram of the compound of formula III (impurity V) obtained in Example 8 of the present invention.

[0055] Figure 6 It is the compound of formula III obtained in Example 8 of the present invention (impurity V) 1 H NMR spectrum. DETAILED DESCRIPTION

[0056] In the description of the present invention, it should be noted that, in the embodiments, those without specifying specific conditions are carried out according to normal conditions or conditions recommended by the manufacturer. Those without specifying the manufacturer for reagents or instruments used are conventional products that can be obtained by commercial purchase. The description of the following examples is only used to help understand the method of the present invention and its core idea, and is not intended to limit the present invention. It should be noted that for those skilled in the art, without departing from the principle of the present invention, the present invention can also be improved and modified in some ways, and these improvements and modifications also fall within the protection scope of the claims of the present invention.

[0057] The synthetic route of cisatracurium besylate impurities and intermediates thereof used in the specific embodiment of the present invention is as follows:

[0058] ;

[0059] as well as

[0060]

[0061] In the embodiments and comparative examples of the present invention, the method for measuring purity is:

[0062] Diluent: acetonitrile: potassium dihydrogen phosphate solution (weigh 6.8 g of potassium dihydrogen phosphate, dissolve it in 1 L of water, and adjust its pH to 3.1 with phosphoric acid) = 20:80.

[0063] Take this product, add diluent to dissolve and dilute to make a solution containing 0.6 mg per 1 ml as the test solution.

[0064] Chromatographic column: ACQUITY UPLC BEH C18 1.7 μm 2.1 × 100 mm;

[0065] Column temperature: 35°C;

[0066] Mobile phase: Mobile phase A: methanol: acetonitrile: potassium dihydrogen phosphate solution (6.8 g / L) (V:V:V) = 5:15:80;

[0067] Mobile phase B: methanol: acetonitrile (V:V) = 30:70;

[0068] Flow rate: 0.5 mL / min;

[0069] Detection wavelength: 280nm;

[0070] Injection volume: 2 μL;

[0071] Sample pan temperature: 6℃±2℃;

[0072] The above chromatographic conditions were used for the test and the area normalization method was used for calculation.

[0073] The present invention is further described in detail below in conjunction with the accompanying drawings and specific embodiments, which are intended to explain the present invention rather than to limit it.

[0074] Example 1

[0075] Preparation of S-tetrahydropapaverine-N-acetyl-L-leucine salt

[0076] Add 9.6 kg of purified water to a 50 L glass reactor, start stirring, add 3.5 kg of tetrahydropapaverine hydrochloride, stir for 10 minutes, add 6.2 kg of toluene, stir for 20 minutes, adjust pH ≥ 9 with 3.0 kg of ammonia water, stir for 15-20 minutes, let stand for 30 minutes after the material is dissolved, and separate; transfer the water layer to another 50 L glass reactor, add 3.5 kg of toluene, stir for 15 minutes, let stand for 30 minutes to separate, combine the toluene layers, add 6.0 kg of purified water, stir for 15 minutes, let stand for 30 minutes to separate, discard the water layer, add 0. 6kg, stir at room temperature for 1 hour, filter, transfer the filtrate to a 100L glass kettle, set the jacket temperature of the reactor to 60±5℃, vacuum degree ≥0.085MPa, and distill under reduced pressure until no continuous droplets are distilled out, add 39.7kg of anhydrous ethanol to the kettle, control the jacket temperature to 55±5℃ and stir to dissolve all the solids, add 1.63kg of N-acetyl-L-leucine after it is dissolved, raise the temperature to 80±4℃ and keep the reaction under reflux for 1.5 hours, lower the temperature in the kettle to 15±3℃, start timing when obvious solid precipitation occurs, keep warm for 4 hours, centrifuge and filter, and treat the filter cake and filtrate A separately.

[0077] After drying the filter cake, 2.2 kg of off-white solid was obtained, and liquid phase detection showed that the S configuration accounted for 81.2%. 17.5 kg of ethanol was used to dissolve the solid by stirring at 75-80 ° C, and then the temperature was naturally lowered to 45 ° C and stirred for 0.5 hours, and the solid was filtered under reduced pressure, and the filter cake was rinsed with 3.0 kg of anhydrous ethanol. The filter cake was vacuum dried at 45 ° C for 12 hours to obtain 1.4 kg of S-tetrahydropapaverine-N-acetyl-L-leucine salt, with a yield of 29.3%, a chemical purity of 100%, and an optical purity of 99.9%.

[0078] Example 2

[0079] Preparation of R-tetrahydropapaverine-N-acetyl-L-leucine salt

[0080] The filtrate A in Example 1 (the liquid phase shows that the R configuration is 79.2%) is transferred to a 100L glass kettle, and the jacket temperature is 50±5°C, the vacuum degree is ≥0.085MPa, and the concentrated product is obtained by vacuum distillation until no continuous fraction is distilled out. 58.9kg of acetone is added, and the jacket temperature is controlled to be 60±5°C and the temperature is raised to reflux state. After stirring to dissolve most of the solid, 0.6kg of purified water is added and stirred until the solution is clear; after the solution is clear, the temperature is gradually reduced to 25°C for crystallization. After the solid is obviously precipitated, the temperature is kept at 23-26°C for 3.5 hours, and the filter cake is filtered under reduced pressure. The filter cake is rinsed with 0.8kg of acetone below 10°C, and 1.25kg of white solid is obtained after drying, which is R-tetrahydropapaverine-N-acetyl-L-leucine salt, with a yield of 26.2%. Sampling and testing show that the chemical purity is 100% and the optical purity is 99.9%.

[0081] Example 3

[0082] Preparation of compound of formula IV (S-cis ester)

[0083] Add 11.2 kg of purified water, 11.2 kg of toluene, and 1.25 kg of S-tetrahydropapaverine-N-acetyl-L-leucine salt to a 100 L glass reactor, stir at room temperature for 20 to 25 minutes, add 0.96 kg of concentrated ammonia water to adjust the pH to ≥ 9, and stir for 10 to 20 minutes to dissolve the materials; after dissolving, let it stand for 15 to 20 minutes, separate the layers, transfer the water layer to a 50 L glass reactor, add 3.75 kg of toluene to the water layer, stir for 15 minutes, let it stand for 30 minutes to separate the layers; discard the water layer, combine the organic layers into a 100 L glass reactor, add 3.75 kg of purified water, and stir for 15 minutes The mixture was stirred for 1 hour at room temperature, filtered, and the filter cake was rinsed with 0.5 kg of toluene. The filtrate was transferred to a 50 L glass kettle, and the jacket temperature was controlled to be 60 ± 5 ° C and the vacuum degree was ≥ 0.08 MPa, and the solvent was evaporated under reduced pressure until no continuous droplets were distilled out; 0.63 kg of toluene, 0.77 kg of tert-butyl acrylate, and 0.08 kg of glacial acetic acid were added, and the jacket temperature was set to 60 ± 3 ° C for insulation reaction for 6 hours, and the jacket temperature was controlled to be 55-60 ° C, and the vacuum degree was ≥ 0.85 MPa and concentrated under reduced pressure until no continuous droplets were distilled out.

[0084] Weigh 0.48 kg of oxalic acid and dissolve it in 5.0 kg of acetone, then add 2.0 kg of ethyl acetate to the above acetone solution for later use; add 2.0 kg of ethyl acetate to the concentrated solution in the previous step to dissolve, transfer the condensate ethyl acetate solution to the oxalic acid solution, start stirring, solid precipitates, stir for 60 minutes, cool to 10±3°C, stir and crystallize for 6 hours. Filter, rinse the filter cake with 0.63 kg of acetone, and dry the filter cake to obtain about 1.17 kg of S-condensate oxalate.

[0085] In a 100L stainless steel reactor, 10.5kg of purified water, 1.17kg of S-condensate oxalate, and 10.5kg of toluene were added, and 0.80kg of ammonia water was added under stirring, and the pH was adjusted to ≥9.0. Stir for 30 minutes, let stand for 30 minutes, separate the layers, transfer the aqueous layer to a 50L glass reactor, add 3.5kg of toluene, stir for 10-20 minutes, let stand for 30 minutes, separate the layers, discard the aqueous layer, combine the organic layers into a 100L stainless steel reactor, add 3.5kg of purified water, stir for 10-20 minutes, let stand for 30 minutes, separate the layers, discard the aqueous layer, add 0.55kg of anhydrous sodium sulfate to the organic layer, stir at room temperature for 10-20 minutes, filter, and filter. The liquid was transferred to a 50L stainless steel reactor, the jacket temperature of the reactor was set to 55-60°C, and the vacuum degree was ≥0.85MPa, and the mixture was concentrated under reduced pressure until no continuous droplets were dripped; 0.64kg of methyl benzenesulfonate and 0.35kg of acetonitrile were added to the concentrate, and the temperature in the reactor was controlled to be 25-30°C and kept warm for reaction for 15 hours; 1.22kg of ethyl acetate was weighed and added to the reactor, stirred and dissolved, 2.63kg of methyl tert-butyl ether was added under stirring, and crystallization was carried out at 25±3°C for 6 hours; filtration was performed, and the filter cake was rinsed with 0.4kg of methyl tert-butyl ether, and 1.12kg of S-configuration quaternary ammonium salt racemate was obtained after drying. UPLC detection showed that S-cis accounted for 75.0% and S-trans accounted for 24.3%.

[0086] Into a 50L glass kettle, 1.12kg of S-configuration quaternary ammonium salt racemate and 7.05kg of dichloromethane were added, the temperature was raised to above 32°C, and the mixture was stirred and dissolved. 6.23kg of methyl tert-butyl ether was weighed and added to the dichloromethane solution under stirring. The temperature in the kettle was controlled to be 29±2°C and the stirring crystallization was carried out for more than 4 hours (the timing was started when the solid was obviously precipitated); filtered, the filter cake was washed with 0.44kg of methyl tert-butyl ether, and the filtrate was transferred back to the 50L glass kettle, the jacket temperature was controlled to be 30-40°C and concentrated under reduced pressure. When concentrated to dry (solid), 1.65kg of dichloromethane was added, the temperature in the kettle was raised to above 32°C and dissolved, and 3.30kg of ethyl acetate was added, and the temperature in the kettle was controlled to be 29±1°C and the timing was started when there was obvious solid precipitation. The crystallization was incubated for 3h, filtered, 0.37kg of ethyl acetate was used for the filter cake, and after the filter cake was dried, 0.64kg of S-cis-ester crude product was obtained, and the liquid phase showed a purity of 97.2%.

[0087] Into a 10L glass kettle, 1.14kg of dichloromethane and 0.64kg of crude S-cis ester were added. The temperature in the kettle was raised to above 32°C for dissolution. Then 2.28kg of ethyl acetate was added. The temperature in the kettle was controlled at 29±1°C. When obvious solid precipitation occurred, the timing was started. The crystallization was kept warm for 3h, filtered, and the filter cake was washed with 0.26kg of ethyl acetate. The filter cake was vacuum dried at 35°C for 10 hours to obtain 0.46kg of compound IV (S-cis ester), with a yield of 29.5% and a purity of 99.3%.

[0088] Example 4

[0089] Preparation of the compound of formula VI (R-cis ester)

[0090] Add 11.2 kg of purified water, 11.2 kg of toluene, and 1.25 kg of R-tetrahydropapaverine-N-acetyl-L-leucine salt to a 100 L glass reactor, stir at room temperature for 20 to 25 minutes, add 0.96 kg of concentrated ammonia water to adjust the pH to ≥ 9, and stir for 10 to 20 minutes to dissolve the materials; after dissolving, let it stand for 15 to 20 minutes, separate the layers, transfer the water layer to a 50 L glass reactor, add 3.75 kg of toluene to the water layer, stir for 15 minutes, let it stand for 30 minutes to separate the layers; discard the water layer, combine the organic layers into a 100 L glass reactor, add 3.75 kg of purified water, and stir for 15 minutes The mixture was stirred for 1 hour at room temperature, filtered, and the filter cake was rinsed with 0.5 kg of toluene. The filtrate was transferred to a 50 L glass kettle, and the jacket temperature was controlled to be 60 ± 5 ° C and the vacuum degree was ≥ 0.08 MPa, and the solvent was evaporated under reduced pressure until no continuous droplets were distilled out; 0.63 kg of toluene, 0.77 kg of tert-butyl acrylate, and 0.08 kg of glacial acetic acid were added, and the jacket temperature was set to 60 ± 3 ° C for insulation reaction for 6 hours, and the jacket temperature was controlled to be 55-60 ° C, and the vacuum degree was ≥ 0.85 MPa and concentrated under reduced pressure until no continuous droplets were distilled out.

[0091] Weigh 0.48 kg of oxalic acid and dissolve it in 5.0 kg of acetone, then add 2.0 kg of ethyl acetate to the above acetone solution for later use; add 2.0 kg of ethyl acetate to the concentrated solution in the previous step to dissolve, transfer the condensate ethyl acetate solution to the oxalic acid solution, start stirring, solid precipitates, stir for 60 minutes, cool to 10±3°C, stir and crystallize for 6 hours. Filter, rinse the filter cake with 0.63 kg of acetone, and dry the filter cake to obtain about 1.17 kg of R-condensate oxalate.

[0092] In a 100L stainless steel reactor, 10.5kg of purified water, 1.17kg of R-condensate oxalate, and 10.5kg of toluene were added, and 0.80kg of ammonia water was added under stirring, and the pH was adjusted to ≥9.0. Stir for 30 minutes, let stand for 30 minutes, separate the layers, transfer the aqueous layer to a 50L glass reactor, add 3.5kg of toluene, stir for 10-20 minutes, let stand for 30 minutes, separate the layers, discard the aqueous layer, combine the organic layers into a 100L stainless steel reactor, add 3.5kg of purified water, stir for 10-20 minutes, let stand for 30 minutes, separate the layers, discard the aqueous layer, add 0.55kg of anhydrous sodium sulfate to the organic layer, stir at room temperature for 10-20 minutes, filter, and filter. The liquid was transferred to a 50L stainless steel reactor, the jacket temperature of the reactor was set to 55-60°C, and the vacuum degree was ≥0.85MPa, and the mixture was concentrated under reduced pressure until no continuous droplets were dripped; 0.64kg of methyl benzenesulfonate and 0.35kg of acetonitrile were added to the concentrate, and the temperature in the reactor was controlled to be 25-30°C and kept warm for reaction for 15 hours; 1.22kg of ethyl acetate was weighed and added to the reactor, stirred to dissolve, 2.63kg of methyl tert-butyl ether was added under stirring, and crystallization was carried out at 25±3°C for 6 hours; filtration was performed, and the filter cake was rinsed with 0.4kg of methyl tert-butyl ether, and 1.12kg of R-configuration quaternary ammonium salt racemate was obtained after drying. UPLC detection showed that R-cis accounted for 75.0% and R-trans accounted for 24.3%.

[0093] Put 1.12 kg of R-configuration quaternary ammonium salt racemate and 7.05 kg of dichloromethane into a 50L glass kettle, heat to above 32°C, stir to dissolve, weigh 6.23 kg of methyl tert-butyl ether, add to the dichloromethane solution under stirring, control the temperature in the kettle at 29±2°C, stir and crystallize for more than 4 hours (start timing when solid precipitates obviously); filter, and wash the filter cake with 0.44 kg of methyl tert-butyl ether. The filter cake is marked as B and used for the preparation of the compound of formula VII (R-trans ester) below.

[0094] The filtrate was transferred back to a 50L glass kettle, and the jacket temperature was controlled at 30-40°C and concentrated under reduced pressure. When concentrated to dryness (solid), 1.65 kg of dichloromethane was added, and the temperature in the kettle was raised to above 32°C for dissolution. Then 3.30 kg of ethyl acetate was added, and the temperature in the kettle was controlled at 29±1°C. When obvious solid precipitation occurred, the timing was started, and the crystallization was kept warm for 3 hours. The filter cake was filtered, and 0.37 kg of ethyl acetate was used. After the filter cake was dried, 0.64 kg of R-cis ester crude product was obtained, and the liquid phase showed a purity of 97.2%.

[0095] 1.14 kg of dichloromethane and 0.64 kg of crude R-cis ester were added to a 10L glass kettle. The temperature in the kettle was raised to above 32°C for dissolution. Then 2.28 kg of ethyl acetate was added. The temperature in the kettle was controlled at 29±1°C. When obvious solid precipitation began, the timer was started. The temperature was kept for 3 hours for crystallization. The filter cake was washed with 0.26 kg of ethyl acetate and dried under vacuum at 35°C for 10 hours to obtain 0.46 kg of compound IV (R-cis ester). The yield was 29.5% and the UPLC purity was 99.3%. The NMR spectrum is shown in Figure 1 As shown: 1 H-NMR (600M, DMSO-d6) δ = 1.38 (s, 9H), 2.86-2.89 (m, 1H), 2.94-2.97 (m, 2H), 3.06-3.09 (m, 2 H), 3.25(s, 3H), 3.29(s, 3H), 3.48-3.52(m, 2H), 3.56-3.58(m, 1H), 3.65-3.68(m, 4H), 3.71( s, 3H), 3.73 (s, 3H), 3.86-3.88 (m, 1H), 4.71 (dd, 1H, J=10.8, 4.2Hz), 5.68 (s, 1H), 6.53 (dd, 1H, J=8.4, 1.8Hz), 6.70 (d, 1H, J=1.8Hz), 6.84 (m, 2H), 7.29-7.32 (m, 3H), 7.60-7.62 (m, 2H).

[0096] Example 5

[0097] Preparation of the compound of formula VII (R-trans ester)

[0098] The filter cake B in Example 4 was vacuum dried at 35°C for 10 hours to obtain 0.20 kg of white solid, which was determined to contain 97.7% of R-trans ester by UPLC detection. The solid was dissolved in 0.8 L of dichloromethane at 37°C, and 0.8 L of methyl tert-butyl ether was added to the solution. After cooling to 22°C, it was stirred for 20 minutes, and the filter cake was filtered under reduced pressure and rinsed with 0.20 L of methyl tert-butyl ether. The filter cake was vacuum dried at 35°C for 10 hours to obtain 0.19 kg of compound VII (R-trans ester), which was a white solid with a yield of 12.2% (based on the amount of R-tetrahydropapaverine-N-acetyl-L-leucine salt). UPLC purity was 99.9%. The NMR spectrum is shown in Figure 2 As shown: 1H-NMR (600M, DMSO-d6) δ = 1.38 (s, 9H), 2.85-2.89 (m, 1H), 2.93-2.96 (m, 2H), 3.06-3.08 (m, 2 H), 3.25(s, 3H), 3.28(s, 3H), 3.48-3.51(m, 2H), 3.55-3.58(m, 1H), 3.65-3.69(m, 4H), 3.71( s, 3H), 3.73 (s, 3H), 3.83-3.89 (m, 1H), 4.70 (dd, 1H, J=10.8, 4.2Hz), 5.68 (s, 1H), 6.53 (dd, 1H, J=8.4, 1.8Hz), 6.69 (d, 1H, J=1.8Hz), 6.84 (m, 2H), 7.29-7.32 (m, 3H), 7.60-7.61 (m, 2H).

[0099] Example 6

[0100] Preparation of Formula V Compound (S-cis ester monoesterified compound)

[0101] Add 8.0 g of 70% benzenesulfonic acid aqueous solution, 3.5 g of purified water and 5.0 g (1.0 eq) of compound IV (S-cis ester) to a three-necked flask, control the temperature in the kettle to 40±3°C and stir for about 60 minutes until the solid is completely dissolved, remove the water by rotary evaporation, and then add 20 mL of dichloromethane to dissolve. The solution is dripped into a 60 mL dichloromethane suspension containing 1,5-pentanediol 16.1 g (20 eq) and CaSO4 (17.0 g), stirred at ambient temperature for 18 hours, filtered under reduced pressure, and the filtrate is diluted with 30 mL of dichloromethane, washed with purified water 3×40 mL, dried over anhydrous magnesium sulfate, and rotary evaporated to dryness to obtain 4.6 g of white solid with a yield of 87.9%.

[0102] Example 7

[0103] Preparation of the compound of formula II (impurity S, 1R-cis-1'S-cis atracurium benzenesulfonate)

[0104] Add 8.0g of 70% benzenesulfonic acid aqueous solution, 3.5g of purified water and 5.0g (1.0eq) of compound VI (R-cis ester) to a three-necked flask, control the temperature in the kettle to 40±3°C and stir for about 60 minutes until the solid is completely dissolved, remove the water therefrom by rotary evaporation, and then add 100mL of toluene and 5.23g (1.0eq) of compound V. After installing a water separator and a reflux condenser (a proper amount of 4A molecular sieve is provided in the water separator for water absorption), control the internal temperature at 25-35°C and reflux under reduced pressure for 24 hours, separate the upper layer after standing and discard, dissolve the lower layer with 90mL of dichloromethane, wash 2×65mL with purified water, dry with anhydrous magnesium sulfate, drop into 900mL of methyl tert-butyl ether for crystallization, and filter under reduced pressure to obtain 6.5g of white solid. The crude product was purified by preparative liquid separation, concentrated by rotary evaporation to about 30 mL, dropped into 400 mL of ether for crystallization, filtered under reduced pressure, and the filter cake was vacuum dried at 35°C for 6 hours to obtain 2.3 g of white solid with a yield of 23.8% and a UPLC purity of 98.15%. Figure 3 As shown. Impurity S 1 H NMR spectra Figure 4 shown. 1 H-NMR (600M, DMSO-d6) δ = 1.40-1.43 (m, 2H), 1.67 (quint, 4H, J = 7.2Hz), 2.85-2.89 (m, 2H), 3.06- 3.22(m, 8H), 3.28(s, 6H), 3.36(s, 2H), 3.50(dd, 3H, J=13.2, 4.2Hz), 3.64(s, 6H), 3.71(s, 6H), 3. 73(s, 6H), 3.73-3.92(m, 8H), 4.09-4.14(m, 4H), 4.85(dd, 2H, J=10.2, 4.2Hz), 5.78(s, 2H), 6.57 (dd, 2H, J=8.4, 2.4Hz), 6.61 (d, 2H, J=1.8Hz), 6.85 (m, 4H), 7.28-7.32 (m, 6H), 7.59-7.61 (m, 4H).

[0105] Example 8

[0106] Preparation of the compound of formula III (impurity V, 1R-trans-1'S-cis-atracurium benzenesulfonate)

[0107] Add 8.0g of 70% benzenesulfonic acid aqueous solution, 3.5g of purified water and 5.0g (1.0eq) of compound VII (R-trans ester) to a three-necked flask, control the temperature in the kettle to 40±3°C and stir for about 60 minutes until the solid is completely dissolved, remove the water therein by rotary evaporation, and then add 100mL of toluene and 5.23g (1.0eq) of compound V. After installing a water separator and a reflux condenser (a proper amount of 4A molecular sieve is provided in the water separator for water absorption), the internal temperature is controlled at 25-35°C and the reaction is refluxed under reduced pressure for 24 hours. After standing, the upper layer is separated and discarded, the lower layer is dissolved with 90mL of dichloromethane, washed with 2×65mL of purified water, dried over anhydrous magnesium sulfate, and then dropped into 900mL of ether for crystallization, and filtered under reduced pressure to obtain 6.4g of white solid. The crude product was separated and purified by preparative liquid phase separation, concentrated by rotary evaporation to about 30 mL, dropped into 400 mL of methyl tert-butyl ether for crystallization, filtered under reduced pressure, and the filter cake was vacuum dried at 35°C for 6 hours to obtain 2.0 g of a white solid with a yield of 20.6% and a UPLC purity of 98.31%. Figure 5 The NMR spectrum is shown in Figure 6 shown. 1 H-NMR (600M, DMSO-d6) δ = 1.25-1.30 (m, 2H), 1.53 (quint, 4H, J = 7.2Hz), 2.86-2.90 (m, 2H), 2.98-3.08 ( m, 8H), 3.24 (s, 6H), 3.29 (s, 6H), 3.50-3.59 (m, 6H), 3.64 (s, 6H), 3.67-3.72 (m, 14H), 3.85-3.90 (m, 2H ), 3.97 (t, 4H, J = 6.6Hz), 4.09-4.14 (m, 4H), 4.73 (dd, 1H, J = 10.2, 4.2Hz), 4.93 (dd, 1H, J = 10.2, 4.2Hz) , 5.66 (s, 1H), 5.88 (s, 1H), 6.52-6.70 (m, 4H), 6.82-6.84 (m, 4H), 7.28-7.33 (m, 6H), 7.60-7.62 (m, 4H).

[0108] The above-mentioned embodiments only express several implementation methods of the present invention, and the description thereof is relatively specific and detailed, but it cannot be understood as limiting the scope of the patent of the present invention. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. A method for preparing an intermediate of cisatracurium besylate impurity S and impurity V, characterized in that: The preparation method comprises the following steps: (a) suspending tetrahydropapaverine hydrochloride in toluene and water, adding sufficient ammonia water, stirring to free the mixture, washing, drying and concentrating the mixture; then salifying the mixture with N-acetyl-L-leucine, filtering the mixture to obtain a crude product of S-tetrahydropapaverine-N-acetyl-L-leucine salt, and evaporating the filtrate to obtain a crude product of R-tetrahydropapaverine-N-acetyl-L-leucine salt; (b) recrystallizing the crude S-tetrahydropapaveline-N-acetyl-L-leucine salt and the crude R-tetrahydropapaveline-N-acetyl-L-leucine salt to obtain a refined S-tetrahydropapaveline-N-acetyl-L-leucine salt and a refined R-tetrahydropapaveline-N-acetyl-L-leucine salt; (c) suspending the refined product of S-tetrahydropapaverine-N-acetyl-L-leucine salt in toluene and water, adding sufficient ammonia water, stirring to free it, washing, drying and concentrating it; then firstly carrying out addition condensation reaction with tert-butyl acrylate, after the reaction is completed, reacting the product with oxalic acid to form oxalate and then purifying it; after the oxalate is freed, reacting it with methyl benzenesulfonate to form S-quaternary ammonium salt racemate, and refining it three times to obtain S-cis ester compound; (e) The reaction process of the refined product of R-tetrahydropapaverine-N-acetyl-L-leucine salt is the same as step (c) to obtain an R-quaternary ammonium salt racemic body, which is then purified to obtain an R-cis ester compound and an R-trans ester compound; Formula IV shows an S-cis ester compound, Formula VI shows an R-cis ester compound, and Formula VII shows an R-trans ester compound; Formula IV, Formula VI, Formula VII.

2. The method for preparing the intermediate of cisatracurium besylate impurity S and impurity V according to claim 1, characterized in that: The process of recrystallizing the crude S-tetrahydropapaverine-N-acetyl-L-leucine salt in step (b) comprises: dissolving the crude S-tetrahydropapaverine-N-acetyl-L-leucine salt in 8-10 mL / g of anhydrous ethanol at 80±2° C., then lowering the temperature to below 45° C. and stirring for 30-40 minutes, and filtering to obtain a refined S-tetrahydropapaverine-N-acetyl-L-leucine salt.

3. The method for preparing the intermediate of cisatracurium besylate impurity S and impurity V according to claim 1, characterized in that: The process of recrystallizing the crude R-tetrahydropapavine-N-acetyl-L-leucine salt in step (b) comprises: heating the crude R-tetrahydropapavine-N-acetyl-L-leucine salt with a mixed solvent of acetone and water to dissolve under reflux, gradually cooling to below 25° C. and stirring for 3 to 4 hours, and filtering to obtain a refined R-tetrahydropapavine-N-acetyl-L-leucine salt.

4. The method for preparing the intermediate of cisatracurium besylate impurity S and impurity V according to claim 3, characterized in that: The amount of acetone in the acetone and water mixed solvent is 26-32 mL / g crude product; the amount of water is 0.1-1 mL / g crude product.

5. The method for preparing the intermediate of cisatracurium besylate impurity S and impurity V according to claim 4, characterized in that: The amount of acetone in the acetone and water mixed solvent is 30 mL / g crude product; the amount of water is 0.3 mL / g crude product.

6. The method for preparing the intermediate of cisatracurium besylate impurity S and impurity V according to claim 1, characterized in that: The control conditions of the addition condensation reaction in step (c) include: the reaction solvent is toluene, the catalyst is glacial acetic acid, the reaction temperature is 60±3° C., and the reaction time is 5-7 hours.

7. The method for preparing the intermediate of cisatracurium besylate impurity S and impurity V according to claim 1, characterized in that: The three-time refining process in step (c) comprises: 1) Add dichloromethane to the S-quaternary ammonium salt racemic body and dissolve it at above 32°C, then add methyl tert-butyl ether, and stir and crystallize at 29±2°C. After solid precipitates, continue to keep warm and crystallize for 4h±10min, filter and wash the filter cake with methyl tert-butyl ether. The filter cake is the S-trans ester compound; 2) The filtrate and washing liquid of step 1) are combined and concentrated to dryness, and dichloromethane is added to dissolve, and then ethyl acetate is added and stirred at 29±1°C for crystallization. After solid precipitation, the crystallization is kept warm for 3h±10min, and the crude S-cis ester is obtained after filtration; 3) Add dichloromethane to the crude S-cis ester and dissolve it at above 32°C, then add ethyl acetate, stir and crystallize at 29±1°C, and continue to keep warm and crystallize for 3h±10min after solid precipitates. Filter the solid and wash it with ethyl acetate, and dry it to obtain S-cis ester, i.e., compound IV.

8. The method for preparing the intermediate of cisatracurium besylate impurity S and impurity V according to claim 1, characterized in that: The refining process in step (e) comprises: (1) Add dichloromethane to the R-quaternary ammonium salt racemic body and dissolve it at above 32°C, then add methyl tert-butyl ether, and stir and crystallize at 29±2°C. After solid precipitates, continue to keep warm and crystallize for 4h±10min, filter and wash the filter cake with methyl tert-butyl ether, and collect the filter cake and the mixture of filtrate and washing liquid respectively; (2) dissolving the filter cake in dichloromethane at 37±1°C, adding methyl tert-butyl ether, and cooling the temperature to 22±1°C and stirring for 20±10 min. filtering out the precipitate, and drying to obtain the R-trans ester, i.e., the compound of formula VII; (3) The mixture of the filtrate and the washing liquid is concentrated to dryness, and dichloromethane is added to dissolve it. Ethyl acetate is then added and stirred at 29±1°C for crystallization. After solids are precipitated, the mixture is kept warm for crystallization for 3h±10min. The crude R-cis ester is obtained after filtration. (4) Add dichloromethane to the crude R-cis ester and dissolve it at above 32°C. Then add ethyl acetate and stir at 29±1°C to crystallize. After solid precipitates, continue to keep the temperature to crystallize for 3h±10min. Filter the solid and wash it with ethyl acetate. After drying, obtain R-cis ester, i.e., compound VI.

9. A method for preparing cisatracurium besylate impurity S and impurity V, characterized in that: The intermediates are prepared by the preparation method according to any one of claims 1 to 8: S-cis ester compound, R-cis ester compound and R-trans ester compound, wherein the S-cis ester compound is shown in formula IV, the R-cis ester compound is shown in formula VI and the R-trans ester compound is shown in formula VII; Formula IV, Formula VI, Formula VII; The preparation method comprises the following steps: i) hydrolyzing the S-cis ester compound in an aqueous benzenesulfonic acid solution at 40±3° C., and reacting the hydrolyzate with 1,5-pentanediol to obtain an S-cis ester monoester compound; ii) The R-cis ester compound is hydrolyzed in a benzenesulfonic acid aqueous solution at 40±3°C, and then the S-cis ester monoester compound is added and stirred in toluene, and refluxed under reduced pressure at 25-35°C for 24 hours±10 minutes, during which the generated water is continuously separated. After the reaction is completed, the mixture is washed and dried, and then dropped into methyl tert-butyl ether for crystallization to obtain a crude product of impurity S. The crude product is recrystallized from diethyl ether to obtain a pure product of impurity S of cisatracurium benzylsulfonate; iii) The R-trans ester compound is hydrolyzed in an aqueous solution of benzenesulfonic acid at 40±3°C, and then the S-cis ester monoester compound is added and stirred in toluene, and refluxed under reduced pressure at 25-35°C for 24 hours±10 minutes, during which the generated water is continuously separated. After the reaction is completed, the compound is washed and dried, and then dropped into ether for crystallization to obtain a crude product of impurity V. The crude product is recrystallized from methyl tert-butyl ether to obtain a pure product of cisatracurium besylate impurity V.

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