CN115850169A - Preparation method of cisatracurium besilate impurity and intermediate thereof - Google Patents
Preparation method of cisatracurium besilate impurity and intermediate thereof Download PDFInfo
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Abstract
The invention provides a method for preparing cisatracurium besilate impurities and an intermediate thereof, wherein the preparation method of the intermediate takes tetrahydropapaverine hydrochloride as an initial raw material, and the tetrahydropapaverine hydrochloride is separated into salt by N-acetyl-L leucine after being dissociated to obtain R-tetrahydropapaverine and S-tetrahydropapaverine; r-tetrahydropapaverine and S-tetrahydropapaverine are condensed with tert-butyl acrylate respectively, the condensation product forms salt with oxalic acid, and then forms quaternary ammonium salt with methyl benzenesulfonate, and three intermediates are obtained after crystallization: an S-cis ester compound, an R-cis ester compound, and an R-trans ester compound. And hydrolyzing the S-cis ester compound, forming a mono-esterification product with 1,5-pentanediol, and esterifying the mono-esterification product with the hydrolysates of the R-cis ester compound and the R-trans ester compound respectively to obtain an impurity S and an impurity V. The compound prepared by the method has high purity, and can be used as an impurity reference substance for quality control of cisatracurium besilate.
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a preparation method of cisatracurium besilate impurities and intermediates thereof.
Background
The cisatracurium besilate is an R-configuration all-cis isomer in 10 chiral isomers of atracurium besilate, and is shown as a formula I. The cisatracurium besilate has great advantages compared with atracurium besilate, including no obvious histamine release, strong 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.
The single chiral configuration drug may have better efficacy than the racemic drug, and may also reduce the dosage and adverse reactions, while reducing the burden of drug metabolism. Cisatracurium besilate has become the mainstream of clinical muscle relaxants based on the above advantages.
The quality of the raw material medicine is a key and source of medicine quality control, wherein the research and control of impurities relate to the clinical safety of the medicine, so the quality control of the raw material medicine becomes one of the key links. The structure of the cisatracurium besilate has 4 chiral centers and 10 chiral isomers in total, and theoretically, the other 9 chiral centers are potential impurities except for the R all-cis configuration (namely, cisatracurium besilate).
The european pharmacopoeia, version 10.0, lists a total of 22 impurities of cisatracurium besilate that need to be controlled, of which 6 impurities belonging to chiral isomers are G, H, S, T, U, V. Wherein G, H is of the configuration 1R-1'R and S, T, U, V these four are of the configuration 1R,1' S. (the 3 impurity structures not listed are all of 1S,1' S configuration, and the probability of generating the three structures is negligibly low from the process route analysis)
Wherein the impurity S is 1R-cis-1'S-cis atracurium besylate as shown in formula II
The impurity V is 1R-trans-1'S-cis atracurium besylate, as shown in formula III
The impurities adopted in the existing quality control of the cisatracurium besilate are imported standard products, the price is extremely high, and the impurities are used in each batch, so the cost is greatly improved to a certain extent.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a preparation method of cisatracurium besilate impurity and an intermediate thereof. The technical scheme of the invention is as follows:
in a first aspect, the invention provides a preparation method of an intermediate of cisatracurium besilate impurity S and impurity V, wherein tetrahydropapaverine hydrochloride is used as a starting material, N-acetyl-L leucine is used for salt formation and resolution after dissociation, and R-tetrahydropapaverine and S-tetrahydropapaverine are obtained; r-tetrahydropapaverine and S-tetrahydropapaverine are condensed with tert-butyl acrylate respectively, and then form quaternary ammonium salt with methyl benzenesulfonate, and three intermediates are obtained after crystallization: formula IV shows S-cis ester compounds, formula VI shows R-cis ester compounds and formula VII shows R-trans ester compounds;
the specific reaction equation is as follows:
and the number of the first and second groups,
further, the preparation method comprises the following steps:
(a) Suspending tetrahydropapaverine hydrochloride in toluene and water, adding sufficient ammonia water, stirring for dissociation, washing, drying, and concentrating; then salifying and crystallizing with N-acetyl-L-leucine, filtering to obtain crude S-tetrahydropapaverine-N-acetyl-L-leucine salt, evaporating the filtrate to dryness to obtain crude R-tetrahydropapaverine-N-acetyl-L-leucine salt;
(b) Recrystallizing the crude S-tetrahydropapaverine-N-acetyl-L-leucine salt and the crude R-tetrahydropapaverine-N-acetyl-L-leucine salt respectively to obtain refined S-tetrahydropapaverine-N-acetyl-L-leucine salt and refined R-tetrahydropapaverine-N-acetyl-L-leucine salt;
(c) Suspending S-tetrahydropapaverine-N-acetyl-L-leucine salt in toluene and water, adding sufficient ammonia water, stirring for dissociation, washing, drying, and concentrating; then carrying out addition condensation reaction with tert-butyl acrylate, and purifying after the reaction is finished, wherein the product and oxalic acid are converted into oxalate; after the oxalate is dissociated, generating an S-quaternary ammonium salt mixed crystal with methyl benzene sulfonate, and refining for three times to obtain an S-cis ester compound;
(e) The reaction process of the R-tetrahydropapaverine-N-acetyl-L-leucine salt is the same as the step (c), and the R-quaternary ammonium salt mixed isomer is obtained and is refined to obtain the R-cis-ester compound and the R-trans-ester compound.
Further, the molar ratio of tetrahydropapaverine hydrochloride to N-acetyl-L-leucine in the step (a) is 1: (1-1.1).
Further, the control conditions for salt crystallization of the concentrate and the N-acetyl-L-leucine in the step (a) comprise: the salifying temperature is 80 +/-2 ℃, the salifying crystallization solvent is absolute ethyl alcohol, the dosage is 8-12 mL/g of concentrate, and the crystallization temperature is not higher than 15 ℃.
Further, the process of recrystallizing the crude S-tetrahydropapaverine-N-acetyl-L-leucine salt in the step (b) comprises the following steps: dissolving the S-tetrahydropapaverine-N-acetyl-L-leucine salt crude product in absolute ethyl alcohol of 8-10 mL/g crude product at the temperature of 80 +/-2 ℃, then cooling to below 45 ℃, stirring for 30-40 min, and filtering to obtain the S-tetrahydropapaverine-N-acetyl-L-leucine salt refined product.
Further, the process of recrystallizing the crude R-tetrahydropapaverine-N-acetyl-L-leucine salt in the step (b) comprises the following steps: heating and refluxing the crude product of the R-tetrahydropapaverine-N-acetyl-L-leucine salt by using a mixed solvent of acetone and water for dissolving, carrying out gradient cooling to below 25 ℃, stirring for 3-4 h, and filtering to obtain a refined product of the R-tetrahydropapaverine-N-acetyl-L-leucine salt.
Further, the amount of acetone in the mixed solvent of acetone and water is 26-32 mL/g of crude product, preferably 30mL/g of crude product; the amount of water is 0.1-1 mL/g of crude product, preferably 0.3mL/g of crude product.
Preferably, the gradient cooling rate is 10 ℃/h.
Further, the control conditions of the addition condensation reaction in the step (c) include: the reaction solvent is toluene, the catalyst is glacial acetic acid, the reaction temperature is 60 +/-3 ℃, and the reaction time is 5-7 h.
Further, the process of the third refining in the step (c) comprises the following steps:
1) Adding dichloromethane into the S-quaternary ammonium salt mixed spinning body to dissolve at the temperature of more than 32 ℃, adding methyl tert-butyl ether, stirring and crystallizing at the temperature of 29 +/-2 ℃, continuing carrying out heat preservation and crystallization for 4h +/-10 min after solid is separated out, filtering, and washing a filter cake by using the methyl tert-butyl ether, wherein the filter cake is an S-trans ester compound;
2) Combining the filtrate and the washing liquid obtained in the step 1), concentrating to dry, adding dichloromethane for dissolving, adding ethyl acetate, stirring at 29 +/-1 ℃ for crystallization, keeping the temperature for crystallization for 3 hours +/-10 minutes after solid is separated out, and filtering to obtain a crude product of the S-cis-ester;
3) And (3) adding dichloromethane into the S-cis ester crude product to dissolve at a temperature of over 32 ℃, adding ethyl acetate, stirring at a temperature of 29 +/-1 ℃ for crystallization, continuing carrying out heat preservation crystallization for 3h +/-10 min after solid is separated out, filtering the solid, washing with ethyl acetate, and drying to obtain the S-cis ester, namely the compound shown in the formula IV.
Further, the refining process in the step (e) comprises:
(1) Adding dichloromethane into the R-quaternary ammonium salt mixed spinning body to dissolve at the temperature of more than 32 ℃, adding methyl tert-butyl ether, stirring and crystallizing at the temperature of 29 +/-2 ℃, continuing carrying out heat preservation and crystallization for 4h +/-10 min after solids are separated out, filtering, washing a filter cake by using the methyl tert-butyl ether, and respectively collecting the filter cake and a mixed solution of a filtrate and a washing solution;
(2) Dissolving the filter cake in dichloromethane at 37 +/-1 ℃, adding methyl tert-butyl ether, cooling to 22 +/-1 ℃, stirring for 20 +/-10 min, filtering out the precipitate, and drying to obtain R-trans ester, namely the compound shown in the formula VII;
(3) Concentrating the mixed solution of the filtrate and the washing solution to dryness, adding dichloromethane for dissolution, adding ethyl acetate, stirring at 29 +/-1 ℃ for crystallization, keeping the temperature for crystallization for 3h +/-10 min after solids are separated out, and filtering to obtain an R-cis-ester crude product;
(4) And (3) adding dichloromethane into the R-cis ester crude product to dissolve at the temperature of more than 32 ℃, adding ethyl acetate, stirring at the temperature of 29 +/-1 ℃ to crystallize, continuing to perform heat preservation crystallization for 3h +/-10 min after solid is separated out, filtering the solid, washing the filtered solid with ethyl acetate, and drying to obtain the R-cis ester, namely the compound shown in the formula VI.
In a second aspect, the invention provides a method for preparing cisatracurium besilate impurity S and impurity V, which comprises the steps of hydrolyzing an S-cis ester compound, forming a monoester product with 1,5-pentanediol, and esterifying the monoester product with hydrolysates of an R-cis ester compound and an R-trans ester compound respectively to obtain impurity S and impurity V, wherein the structural formulas of the impurity S and the impurity V are as follows:
the specific reaction equation is as follows:
further, the preparation method comprises the following steps:
i) Hydrolyzing S-cis ester in benzenesulfonic acid aqueous solution at 40 +/-3 ℃, and reacting the hydrolysate with 1,5-pentanediol to prepare an S-cis ester mono-esterified compound;
ii) hydrolyzing the R-cis ester compound in a benzenesulfonic acid aqueous solution at 40 +/-3 ℃, adding an S-cis ester mono-esterified compound in toluene, stirring, carrying out reduced pressure reflux at 25-35 ℃ for 24 hours +/-10 min, continuously separating out generated water during the reaction, washing and drying after the reaction is finished, dripping the water into methyl tert-butyl ether for crystallization to obtain a crude product of the impurity S, and recrystallizing the crude product with diethyl ether to obtain a cis-atracurium besilate impurity S pure product;
iii) Hydrolyzing the R-trans-ester compound in a benzenesulfonic acid aqueous solution at 40 +/-3 ℃, adding the S-cis-ester monoester compound in toluene, stirring, carrying out reduced pressure reflux at 25-35 ℃ for 24 hours +/-10 minutes, continuously separating out generated water, washing and drying after the reaction is finished, dripping into diethyl ether for crystallization to obtain a crude product of the impurity V, and recrystallizing the crude product by methyl tert-butyl ether to obtain the purified product of the cis-atracurium besilate impurity V.
The technical scheme adopted by the invention has safe and reliable synthesis process and good reaction reproducibility, and becomes a method for efficiently preparing cis-atracurium besilate 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 besilate.
Drawings
The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the invention and not to limit the invention. In the drawings:
FIG. 1 shows example 4 of the present inventionOf the compound of formula VI obtained 1 H nuclear magnetic spectrum.
FIG. 2 is a diagram of the compound of formula VII obtained in example 5 of the present invention 1 H nuclear magnetic spectrum.
FIG. 3 is a UPLC chromatogram of the compound of formula II (impurity S) obtained in example 7 according to the present invention.
FIG. 4 shows the compound of formula II (impurity S) obtained in example 7 of the present invention 1 H nuclear magnetic spectrum.
FIG. 5 is a UPLC chromatogram of the compound of formula III (impurity V) obtained in example 8 according to the present invention.
FIG. 6 shows the compound of formula III (impurity V) obtained in example 8 of the present invention 1 H nuclear magnetic spectrum.
Detailed Description
In the description of the present invention, it should be noted that those who do not specify specific conditions in the examples are performed according to conventional conditions or conditions recommended by manufacturers. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially. The following examples are only for the purpose of helping understanding the method of the present invention and the core idea thereof, and are not to be construed as limiting the present invention, it should be noted that those skilled in the art can make several improvements and modifications to the present invention without departing from the principle of the present invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention.
The synthesis route of the cisatracurium besilate impurity and the intermediate thereof adopted by the specific embodiment of the invention is as follows:
(ii) a And
in the examples of the present invention and comparative examples, the method of determining purity was:
diluent (b): acetonitrile: potassium dihydrogen phosphate solution (6.8 g of potassium dihydrogen phosphate was weighed out and dissolved in 1L of water, and the pH thereof was adjusted to 3.1 with phosphoric acid) = 20.
Taking the product, adding diluent to dissolve and dilute to prepare a solution containing 0.6mg of the product in each 1ml as a test solution.
A chromatographic column: ACQUITY UPLC BEH C18.7 μm 2.1X 100mm;
column temperature: 35 ℃;
mobile phase: mobile phase A, methanol: acetonitrile: potassium dihydrogen phosphate solution (6.8 g/L) (V: V) = 5;
mobile phase B is methanol: acetonitrile (V: V) = 30;
flow rate: 0.5mL/min;
detection wavelength: 280nm;
sample injection amount: 2 mu L of the solution;
temperature of the sample pan: 6 +/-2 ℃;
and (4) performing the chromatographic condition test and calculating by an area normalization method.
The invention will be described in further detail with reference to the following figures and specific examples, which are given by way of illustration and not by way of limitation.
Example 1
Preparation of S-tetrahydropapaverine-N-acetyl-L-leucine salt
Adding 9.6kg of purified water into a 50L glass reaction kettle, starting stirring, adding 3.5kg of tetrahydropapaverine hydrochloride, stirring for 10 minutes, adding 6.2kg of toluene, stirring for 20 minutes, adjusting the pH to be more than or equal to 9 by using 3.0kg of ammonia water, stirring for 15-20 minutes, standing for 30 minutes after the materials are dissolved and clear, and layering; transferring the water layer into another 50L glass reaction kettle, adding 3.5kg of toluene, stirring for 15 minutes, standing for 30 minutes for layering, combining toluene layers, adding 6.0kg of purified water, stirring for 15 minutes, standing for 30 minutes for layering, discarding the water layer, adding 0.6kg of anhydrous sodium sulfate into the organic layer, stirring for 1 hour at normal temperature, filtering, transferring the filtrate into a 100L glass kettle, setting the temperature of a jacket of the reaction kettle to be 60 +/-5 ℃, distilling under reduced pressure at the vacuum degree of not less than 0.085MPa until no continuous liquid drops are distilled off, adding 39.7kg of anhydrous ethanol into the kettle, controlling the temperature of the jacket to be 55 +/-5 ℃, stirring to completely dissolve the solid, adding 1.63kg of N-acetyl-L-leucine after dissolution, heating to 80 +/-4 ℃, carrying out heat preservation reaction for 1.5 hours under a reflux state, reducing the temperature in the kettle to be 15 +/-3 ℃, starting timing when obvious solid is separated out, carrying out heat preservation for 4 hours, centrifuging and filtering a filter cake, and treating the filtrate A respectively.
2.2kg of white-like solid is obtained after drying the filter cake, and the liquid phase detection proves that the S configuration accounts for 81.2 percent. Stirring and dissolving 17.5kg of ethanol and 75-80 ℃, then naturally cooling, stirring for 0.5 hour after cooling to 45 ℃, filtering under reduced pressure, leaching a filter cake with 3.0kg of absolute ethanol, and vacuum drying the filter cake for 12 hours at 45 ℃ to obtain 1.4kg of S-tetrahydropapaverine-N-acetyl-L-leucine salt, wherein the yield is 29.3%, the chemical purity is 100%, and the optical purity is 99.9%.
Example 2
Preparation of R-tetrahydropapaverine-N-acetyl-L-leucine salt
The filtrate A (liquid phase shows that the R configuration is 79.2%) in example 1 is transferred into a 100L glass kettle, and the vacuum distillation is carried out at the jacket temperature of 50 +/-5 ℃ and the vacuum degree of more than or equal to 0.085MPa until no continuous fraction is distilled off, thus obtaining the concentrate. Adding 58.9kg of acetone, controlling the temperature of a jacket to 60 +/-5 ℃, heating to a reflux state, stirring to dissolve most of solid, adding 0.6kg of purified water, and stirring until the solid is clear; dissolving, gradually cooling to 25 ℃ for crystallization, timing after solid is obviously separated out, keeping the temperature at 23-26 ℃ for 3.5 hours, decompressing and filtering, leaching a filter cake by using 0.8kg of acetone with the temperature of below 10 ℃, and drying to obtain 1.25kg of white solid which is R-tetrahydropapaverine-N-acetyl-L-leucine salt with the yield of 26.2%. And sampling and detecting, wherein the chemical purity is 100 percent, and the optical purity is 99.9 percent.
Example 3
Preparation of the Compound of formula IV (S-cis ester)
Adding 11.2kg of purified water, 11.2kg of toluene and 1.25kg of S-tetrahydropapaverine-N-acetyl-L-leucine salt into a 100L glass kettle, stirring at room temperature for 20-25 minutes, adding 0.96kg of strong ammonia water, adjusting the pH value to be more than or equal to 9, and stirring for 10-20 minutes to dissolve and clear the materials; standing for 15-20 minutes after dissolving and cleaning, layering, transferring the water layer into a 50L glass reaction kettle, adding 3.75kg of toluene into the water layer, stirring for 15 minutes, and standing for 30 minutes for layering; discarding the water layer, combining the organic layers into a 100L glass kettle, adding 3.75kg of purified water, stirring for 15 minutes, standing for 20 minutes, discarding the water layer, adding 0.63kg of anhydrous sodium sulfate into the organic layers, stirring for 1 hour at normal temperature, filtering, and leaching the filter cake with 0.5kg of toluene; transferring the filtrate to a 50L glass kettle, controlling the temperature of a jacket to be 60 +/-5 ℃, and decompressing and steaming the solvent at the vacuum degree of more than or equal to 0.08MPa until no continuous liquid drops are distilled off; adding 0.63kg of toluene, 0.77kg of tert-butyl acrylate and 0.08kg of glacial acetic acid, setting the temperature of a jacket to be 60 +/-3 ℃, carrying out heat preservation reaction for 6 hours, controlling the temperature of the jacket to be 55-60 ℃, and carrying out reduced pressure concentration under the vacuum degree of more than or equal to 0.85MPa until no continuous liquid drops drop.
Weighing 0.48kg of oxalic acid, dissolving in 5.0kg of acetone, and adding 2.0kg of ethyl acetate into the acetone solution for later use; adding 2.0kg of ethyl acetate into the concentrated solution obtained in the last step for dissolving to obtain a condensation compound ethyl acetate solution, transferring the condensation compound ethyl acetate solution into an oxalic acid solution, starting stirring to separate out solids, fully stirring for 60 minutes, cooling to 10 +/-3 ℃, stirring and crystallizing for 6 hours. Filtering, fully leaching the filter cake with 0.63kg of acetone, and drying the filter cake to obtain about 1.17kg of S-condensation product oxalate.
Adding 10.5kg of purified water and 1.17kg of S-condensation product oxalate into a 100L stainless steel reaction kettle, adding 10.5kg of toluene, adding 0.80kg of ammonia water under stirring, adjusting the pH value to be more than or equal to 9.0, stirring for 30 minutes, standing for 30 minutes, layering, transferring a water layer into a 50L glass reaction kettle, adding 3.5kg of toluene, stirring for 10-20 minutes, standing for 30 minutes, layering, removing a water layer, combining an organic layer into a 100L stainless steel reaction kettle, adding 3.5kg of purified water, stirring for 10-20 minutes, standing for 30 minutes, layering, removing a water layer, adding 0.55kg of anhydrous sodium sulfate into the organic layer, stirring for 10-20 minutes at normal temperature, filtering, transferring a filtrate into a 50L stainless steel reaction kettle, setting the jacket temperature of the reaction kettle to be 55-60 ℃, and concentrating under the vacuum degree of more than or equal to 0.85MPa until no continuous liquid drops drop; 0.64kg of methyl benzenesulfonate and 0.35kg of acetonitrile are added into the concentrate, and the temperature in the kettle is controlled to be 25-30 ℃ for heat preservation reaction for 15 hours; weighing 1.22kg of ethyl acetate, putting into a reaction kettle, stirring for dissolving, adding 2.63kg of methyl tert-butyl ether under stirring, stirring for crystallizing at 25 +/-3 ℃ for 6 hours; filtering, leaching a filter cake with 0.4kg of methyl tert-butyl ether, drying to obtain 1.12kg of S-configuration quaternary ammonium salt mixed spinning body, and detecting by UPLC that S-cis accounts for 75.0% and S-trans accounts for 24.3%.
Adding 1.12kg of S-configuration quaternary ammonium salt mixed rotary body and 7.05kg of dichloromethane into a 50L glass kettle, heating to above 32 ℃, stirring for dissolving, weighing 6.23kg of methyl tert-butyl ether, adding into a dichloromethane solution under stirring, controlling the temperature in the kettle to be 29 +/-2 ℃, stirring for crystallizing for more than 4 hours (timing when solid is obviously separated out); filtering, washing a filter cake with 0.44kg of methyl tert-butyl ether, transferring a filtrate into a 50L glass kettle, controlling the temperature of a jacket to be 30-40 ℃, carrying out reduced pressure concentration, adding 1.65kg of dichloromethane when the concentration is dry (solid), heating the temperature in the kettle to be above 32 ℃ for dissolution, adding 3.30kg of ethyl acetate, controlling the temperature in the kettle to be 29 +/-1 ℃, starting timing when obvious solid is separated out, carrying out thermal insulation crystallization for 3 hours, filtering, using 0.37kg of ethyl acetate for the filter cake, drying the filter cake to obtain 0.64kg of S-cis-ester crude product, wherein the liquid phase shows that the purity is 97.2%.
Adding 1.14kg of dichloromethane and 0.64kg of S-cis ester crude product into a 10L glass kettle, heating the temperature in the kettle to be above 32 ℃ for dissolution, then adding 2.28kg of ethyl acetate, controlling the temperature in the kettle to be 29 +/-1 ℃ until obvious solid is separated out, keeping the temperature for crystallization for 3h, filtering, washing a filter cake by using 0.26kg of ethyl acetate, and drying the filter cake in vacuum at 35 ℃ for 10 h to obtain 0.46kg of a compound (S-cis ester) in the formula IV, wherein the yield is 29.5% and the purity is 99.3%.
Example 4
Preparation of the Compound of formula VI (R-cis ester)
Adding 11.2kg of purified water, 11.2kg of toluene and 1.25kg of R-tetrahydropapaverine-N-acetyl-L-leucine salt into a 100L glass kettle, stirring at room temperature for 20-25 minutes, adding 0.96kg of strong ammonia water, adjusting the pH value to be more than or equal to 9, and stirring for 10-20 minutes to dissolve and clear the materials; standing for 15-20 minutes after dissolving and cleaning, layering, transferring the water layer into a 50L glass reaction kettle, adding 3.75kg of toluene into the water layer, stirring for 15 minutes, and standing for 30 minutes for layering; discarding the water layer, combining the organic layers into a 100L glass kettle, adding 3.75kg of purified water, stirring for 15 minutes, standing for 20 minutes, discarding the water layer, adding 0.63kg of anhydrous sodium sulfate into the organic layers, stirring for 1 hour at normal temperature, filtering, and leaching the filter cake with 0.5kg of toluene; transferring the filtrate to a 50L glass kettle, controlling the temperature of a jacket to be 60 +/-5 ℃, and decompressing and steaming the solvent at the vacuum degree of more than or equal to 0.08MPa until no continuous liquid drops are distilled off; adding 0.63kg of toluene, 0.77kg of tert-butyl acrylate and 0.08kg of glacial acetic acid, setting the temperature of a jacket to be 60 +/-3 ℃, carrying out heat preservation reaction for 6 hours, controlling the temperature of the jacket to be 55-60 ℃, and carrying out reduced pressure concentration under the vacuum degree of more than or equal to 0.85MPa until no continuous liquid drops drop.
Weighing 0.48kg of oxalic acid, dissolving in 5.0kg of acetone, and adding 2.0kg of ethyl acetate into the acetone solution for later use; adding 2.0kg of ethyl acetate into the concentrated solution obtained in the last step for dissolving to obtain a condensation compound ethyl acetate solution, transferring the condensation compound ethyl acetate solution into an oxalic acid solution, starting stirring to separate out solids, fully stirring for 60 minutes, cooling to 10 +/-3 ℃, stirring and crystallizing for 6 hours. Filtering, fully leaching the filter cake with 0.63kg of acetone, and drying the filter cake to obtain about 1.17kg of the oxalate of the R-condensation compound.
Adding 10.5kg of purified water and 1.17kg of R-condensation product oxalate into a 100L stainless steel reaction kettle, adding 10.5kg of toluene, adding 0.80kg of ammonia water under stirring, adjusting the pH value to be more than or equal to 9.0, stirring for 30 minutes, standing for 30 minutes, layering, transferring a water layer into a 50L glass reaction kettle, adding 3.5kg of toluene, stirring for 10-20 minutes, standing for 30 minutes, layering, removing a water layer, combining an organic layer into a 100L stainless steel reaction kettle, adding 3.5kg of purified water, stirring for 10-20 minutes, standing for 30 minutes, layering, removing a water layer, adding 0.55kg of anhydrous sodium sulfate into the organic layer, stirring for 10-20 minutes at normal temperature, filtering, transferring a filtrate into a 50L stainless steel reaction kettle, setting the jacket temperature of the reaction kettle to be 55-60 ℃, and concentrating under the vacuum degree of more than or equal to 0.85MPa until no continuous liquid drops drop; 0.64kg of methyl benzenesulfonate and 0.35kg of acetonitrile are added into the concentrate, and the temperature in the kettle is controlled to be 25-30 ℃ for heat preservation reaction for 15 hours; weighing 1.22kg of ethyl acetate, putting into a reaction kettle, stirring for dissolving, adding 2.63kg of methyl tert-butyl ether under stirring, stirring for crystallizing at 25 +/-3 ℃ for 6 hours; filtering, leaching the filter cake with 0.4kg of methyl tert-butyl ether, drying to obtain 1.12kg of R-configuration quaternary ammonium salt mixed spinning body, and detecting by UPLC, wherein the R-cis accounts for 75.0% and the R-trans accounts for 24.3%.
Adding 1.12kg of R-configuration quaternary ammonium salt mixed rotary body and 7.05kg of dichloromethane into a 50L glass kettle, heating to above 32 ℃, stirring for dissolving, weighing 6.23kg of methyl tert-butyl ether, adding into a dichloromethane solution under stirring, controlling the temperature in the kettle to be 29 +/-2 ℃, stirring for crystallizing for more than 4 hours (timing when solid is obviously separated out); filtration was carried out and the filter cake was washed with 0.44kg of methyl tert-butyl ether. The filter cake, designated B, was used in the preparation of the compound of formula VII (R-trans ester) below.
Transferring the filtrate back to a 50L glass kettle, controlling the temperature of a jacket to be 30-40 ℃, carrying out reduced pressure concentration, adding 1.65kg of dichloromethane when the concentration is dry (solid), heating the temperature in the kettle to be more than 32 ℃ for dissolution, adding 3.30kg of ethyl acetate, controlling the temperature in the kettle to be 29 +/-1 ℃, timing when obvious solid is separated out, carrying out thermal insulation crystallization for 3 hours, filtering, using 0.37kg of ethyl acetate to filter cakes, drying the filter cakes to obtain 0.64kg of R-cis-ester crude product, wherein the liquid phase shows that the purity is 97.2%.
Adding 1.14kg of dichloromethane and 0.64kg of crude product of the R-cis-ester into a 10L glass kettle, heating the temperature in the kettle to be above 32 ℃ for dissolution, then adding 2.28kg of ethyl acetate, controlling the temperature in the kettle to be 29 +/-1 ℃ and timing when obvious solid is separated out, carrying out thermal insulation crystallization for 3h, filtering, washing a filter cake by using 0.26kg of ethyl acetate, and carrying out vacuum drying on the filter cake at 35 ℃ for 10 h to obtain 0.46kg of the compound (R-cis-ester) in the formula IV, wherein the yield is 29.5 percent and the purity of UPLC is 99.3 percent. The nuclear magnetic spectrum is shown in figure 1: 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，2H)，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)。
example 5
Preparation of the Compound of formula VII (R-trans ester)
The filter cake B from example 4 was dried under vacuum at 35 ℃ for 10 hours to give 0.20kg of a white solid which was judged to contain 97.7% by UPLC assay to contain R-trans ester, the solid was dissolved in 0.8L of dichloromethane at 37 ℃, 0.8L of methyl tert-butyl ether was added to the solution, the solution was cooled to 22 ℃ and stirred for a further 20 minutes, filtered under reduced pressure, the filter cake was rinsed with 0.20L of methyl tert-butyl ether and dried under vacuum at 35 ℃ for 10 hours to give 0.19kg of the compound of formula VII (R-trans ester) as a white solid in 12.2% yield (based on the R-tetrahydropapaverine-N-acetyl-L-leucine salt charge). UPLC purity 99.9%. The nuclear magnetic spectrum is shown in figure 2: 1 H-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，2H)，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)。
example 6
Preparation of the Compound of formula V (S-cis ester monoesterified Compound)
8.0g of a 70% benzenesulfonic acid aqueous solution, 3.5g of purified water and 5.0g (1.0 eq) of the compound of formula IV (S-cis ester) were charged into a three-necked flask, and the mixture was stirred at 40. + -. 3 ℃ for about 60 minutes while controlling the temperature in the flask until the solid was completely dissolved, and then the solid was dissolved by rotary evaporation to remove water therefrom, followed by addition of 20mL of methylene chloride. The solution was added dropwise to 16.1g (20 eq) of CaSO containing 1,5-pentanediol 4 (17.0 g) in 60mL dichloromethane suspension, ambient temperature stirring for 18 hours, vacuum filtration, filtrate added 30mL dichloromethane dilution, purified water washing 3X 40mL, anhydrous magnesium sulfate drying, rotary evaporation to dryness, white solid 4.6g, yield 87.9%.
Example 7
Preparation of Compound of formula II (impurity S, 1R-cis-1'S-cis atracurium besylate)
A three-necked flask was charged with 8.0g of a 70% benzenesulfonic acid aqueous solution, 3.5g of purified water and 5.0g (1.0 eq) of the compound of formula VI (R-cis ester), stirred at 40. + -. 3 ℃ for about 60 minutes while controlling the temperature in the flask until the solid was completely dissolved, and then subjected to rotary evaporation to remove water therefrom, followed by addition of 100mL of toluene and 5.23g (1.0 eq) of the compound of formula V. After a water separator and a reflux condenser pipe are arranged in the device (a proper amount of 4A molecular sieve is arranged in the water separator for absorbing water), the internal temperature is controlled at 25-35 ℃ for 24 hours under reduced pressure and reflux reaction, the upper layer is separated and discarded after standing, the lower layer is dissolved by 90mL of dichloromethane, 2X 65mL of purified water is washed, after being dried by anhydrous magnesium sulfate, the purified water is dropped into 900mL of methyl tert-butyl ether for crystallization, and the white solid 6.5g is obtained after reduced pressure suction filtration. Separating and purifying the crude product by a prepared liquid phase, concentrating to about 30mL by rotary evaporation, dripping into 400mL of diethyl ether for crystallization, filtering under reduced pressure, and vacuum drying the filter cake at 35 ℃ for 6 hours to obtain a white solid2.3g of the product, yield 23.8% and UPLC purity 98.15%, as shown in FIG. 3. Of impurities S 1 The H nuclear magnetic spectrum is shown in FIG. 4. 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)。
Example 8
Preparation of Compound of formula III (impurity V, 1R-trans-1'S-cis atracurium besylate)
A three-necked flask was charged with 8.0g of a 70% benzenesulfonic acid aqueous solution, 3.5g of purified water and 5.0g (1.0 eq) of the compound of formula VII (R-trans ester), stirred at 40. + -. 3 ℃ for about 60 minutes while controlling the temperature in the flask until the solid was completely dissolved, and then subjected to rotary evaporation to remove water therefrom, followed by addition of 100mL of toluene and 5.23g (1.0 eq) of the compound of formula V. After a water separator and a reflux condenser pipe are arranged in the device (a proper amount of 4A molecular sieve is arranged in the water separator for absorbing water), the internal temperature is controlled at 25-35 ℃ for 24 hours, the pressure reduction reflux reaction is carried out, the upper layer is separated and discarded after the standing, the lower layer is dissolved by 90mL dichloromethane, 2X 65mL of purified water is washed, after the drying by anhydrous magnesium sulfate, the purified water is dripped into 900mL ether for crystallization, and the pressure reduction suction filtration is carried out, thus obtaining 6.4g of white solid. The crude product was separated and purified by preparative liquid phase separation, concentrated to about 30mL by rotary evaporation, dropped into 400mL methyl tert-butyl ether for crystallization, vacuum filtered, and the filter cake was vacuum dried at 35 ℃ for 6 hours to give 2.0g of white solid with a yield of 20.6% and a purity of 98.31% for UPLC as shown in FIG. 5. The NMR spectrum is shown in FIG. 6. 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)。
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the present invention. It should be noted that various changes and modifications can be made by those skilled in the art without departing from the spirit of the invention, and these changes and modifications are all within the scope of the invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (10)
1. The preparation method of the cisatracurium besilate impurity S and impurity V intermediate is characterized by comprising the following steps: taking tetrahydropapaverine hydrochloride as an initial raw material, dissociating, and then salifying and splitting by using N-acetyl-L leucine to obtain R-tetrahydropapaverine and S-tetrahydropapaverine; r-tetrahydropapaverine and S-tetrahydropapaverine are condensed with tert-butyl acrylate respectively, and then form quaternary ammonium salt with methyl benzenesulfonate, and three intermediates are obtained after crystallization: formula IV shows S-cis ester compounds, formula VI shows R-cis ester compounds and formula VII shows R-trans ester compounds;
the specific reaction equation is as follows:
and the number of the first and second groups,
2. the process for the preparation of cisatracurium besilate impurity S and impurity V intermediates according to claim 1, characterized in that: the preparation method comprises the following steps:
(a) Suspending tetrahydropapaverine hydrochloride in toluene and water, adding sufficient ammonia water, stirring for dissociation, washing, drying, and concentrating; then salifying and crystallizing with N-acetyl-L-leucine, filtering to obtain crude S-tetrahydropapaverine-N-acetyl-L-leucine salt, evaporating the filtrate to dryness to obtain crude R-tetrahydropapaverine-N-acetyl-L-leucine salt;
(b) Recrystallizing the crude S-tetrahydropapaverine-N-acetyl-L-leucine salt and the crude R-tetrahydropapaverine-N-acetyl-L-leucine salt respectively to obtain refined S-tetrahydropapaverine-N-acetyl-L-leucine salt and refined R-tetrahydropapaverine-N-acetyl-L-leucine salt;
(c) Suspending S-tetrahydropapaverine-N-acetyl-L-leucine salt in toluene and water, adding sufficient ammonia water, stirring for dissociation, washing, drying, and concentrating; then carrying out addition condensation reaction with tert-butyl acrylate, and purifying after the reaction is finished, wherein the product and oxalic acid are converted into oxalate; after the oxalate is dissociated, generating an S-quaternary ammonium salt mixed crystal with methyl benzene sulfonate, and refining for three times to obtain an S-cis ester compound;
(e) The reaction process of the R-tetrahydropapaverine-N-acetyl-L-leucine salt is the same as the step (c), and the R-quaternary ammonium salt mixed isomer is obtained and is refined to obtain the R-cis-ester compound and the R-trans-ester compound.
3. The process for the preparation of cisatracurium besilate impurity S and impurity V intermediates according to claim 2, characterized in that: the process for recrystallizing the crude S-tetrahydropapaverine-N-acetyl-L-leucine salt in the step (b) comprises the following steps: dissolving the crude product of the S-tetrahydropapaverine-N-acetyl-L-leucine salt in absolute ethyl alcohol of 8-10 mL/g of the crude product at the temperature of 80 +/-2 ℃, then cooling the temperature to below 45 ℃, stirring for 30-40 min, and filtering to obtain the refined product of the S-tetrahydropapaverine-N-acetyl-L-leucine salt.
4. The method for preparing cis atracurium besilate impurity S and impurity V intermediates according to claim 2, characterized in that: the process for recrystallizing the crude product of the R-tetrahydropapaverine-N-acetyl-L-leucine salt in the step (b) comprises the following steps: heating and refluxing the R-tetrahydropapaverine-N-acetyl-L-leucine salt crude product with a mixed solvent of acetone and water for dissolving, performing gradient cooling to below 25 ℃, stirring for 3-4 h, and filtering to obtain a refined product of the R-tetrahydropapaverine-N-acetyl-L-leucine salt.
5. The method for preparing cis atracurium besilate impurity S and impurity V intermediates according to claim 4, characterized in that: the using amount of acetone in the mixed solvent of acetone and water is 26-32 mL/g of crude product, and preferably 30mL/g of crude product; the amount of water is 0.1-1 mL/g of crude product, preferably 0.3mL/g of crude product.
6. The method for preparing cis atracurium besilate impurity S and impurity V intermediates according to claim 2, characterized in that: the control conditions of the addition condensation reaction in the step (c) comprise: the reaction solvent is toluene, the catalyst is glacial acetic acid, the reaction temperature is 60 +/-3 ℃, and the reaction time is 5-7 h.
7. The process for the preparation of cisatracurium besilate impurity S and impurity V intermediates according to claim 2, characterized in that: the process of the third refining in the step (c) comprises the following steps:
1) Adding dichloromethane into the S-quaternary ammonium salt mixed spinning body to dissolve at the temperature of more than 32 ℃, adding methyl tert-butyl ether, stirring and crystallizing at the temperature of 29 +/-2 ℃, continuing carrying out heat preservation and crystallization for 4h +/-10 min after solid is separated out, filtering, and washing a filter cake by using the methyl tert-butyl ether, wherein the filter cake is an S-trans ester compound;
2) Combining the filtrate and the washing liquid in the step 1), concentrating to dry, adding dichloromethane for dissolution, adding ethyl acetate, stirring at 29 +/-1 ℃ for crystallization, keeping the temperature for crystallization for 3h +/-10 min after solid is separated out, and filtering to obtain an S-cis-ester crude product;
3) And (3) adding dichloromethane into the S-cis ester crude product to dissolve at the temperature of more than 32 ℃, adding ethyl acetate, stirring at the temperature of 29 +/-1 ℃ to crystallize, continuing to crystallize at the temperature of 3h +/-10 min after solid is separated out, filtering the solid, washing the solid with ethyl acetate, and drying to obtain the S-cis ester, namely the compound shown in the formula IV.
8. The method for preparing cis atracurium besilate impurity S and impurity V intermediates according to claim 2, characterized in that: the refining process in the step (e) comprises the following steps:
(1) Adding dichloromethane into the R-quaternary ammonium salt mixed spinning body to dissolve at the temperature of more than 32 ℃, adding methyl tert-butyl ether, stirring and crystallizing at the temperature of 29 +/-2 ℃, continuing carrying out heat preservation and crystallization for 4h +/-10 min after solids are separated out, filtering, washing a filter cake by using the methyl tert-butyl ether, and respectively collecting the filter cake and a mixed solution of a filtrate and a washing solution;
(2) Dissolving the filter cake in dichloromethane at 37 +/-1 ℃, adding methyl tert-butyl ether, cooling to 22 +/-1 ℃, stirring for 20 +/-10 min, filtering out the precipitate, and drying to obtain R-trans ester, namely the compound shown in the formula VII;
(3) Concentrating the mixed solution of the filtrate and the washing solution to dryness, adding dichloromethane for dissolution, adding ethyl acetate, stirring at 29 +/-1 ℃ for crystallization, keeping the temperature for crystallization for 3h +/-10 min after solids are separated out, and filtering to obtain an R-cis-ester crude product;
(4) And (3) adding dichloromethane into the R-cis ester crude product to dissolve at the temperature of more than 32 ℃, adding ethyl acetate, stirring at the temperature of 29 +/-1 ℃ to crystallize, continuing to perform heat preservation crystallization for 3h +/-10 min after solid is separated out, filtering the solid, washing the filtered solid with ethyl acetate, and drying to obtain the R-cis ester, namely the compound shown in the formula VI.
9. The preparation method of the cisatracurium besilate impurity S and the impurity V is characterized by comprising the following steps of: is prepared from an intermediate as claimed in any one of claims 1 to 8, by a process comprising: hydrolyzing the S-cis ester compound, forming a mono-esterification product with 1,5-pentanediol, and esterifying the mono-esterification product with the hydrolysates of the R-cis ester compound and the R-trans ester compound respectively to obtain an impurity S and an impurity V, wherein the structural formulas of the impurity S and the impurity V are as follows:
the specific reaction equation is as follows:
10. the method of preparing cisatracurium besilate impurity S and impurity V according to claim 9, characterized in that: the preparation method comprises the following steps:
i) Hydrolyzing S-cis ester in benzenesulfonic acid aqueous solution at 40 +/-3 ℃, and reacting the hydrolysate with 1,5-pentanediol to prepare an S-cis ester mono-esterified compound;
ii) hydrolyzing the R-cis ester compound in a benzenesulfonic acid aqueous solution at 40 +/-3 ℃, adding an S-cis ester mono-esterified compound in toluene, stirring, carrying out reduced pressure reflux at 25-35 ℃ for 24 hours +/-10 min, continuously separating out generated water during the reaction, washing and drying after the reaction is finished, dripping the water into methyl tert-butyl ether for crystallization to obtain a crude product of the impurity S, and recrystallizing the crude product with diethyl ether to obtain a cis-atracurium besilate impurity S pure product;
iii) Hydrolyzing the R-trans-ester compound in a benzenesulfonic acid aqueous solution at 40 +/-3 ℃, adding the S-cis-ester monoester compound in toluene, stirring, carrying out reduced pressure reflux at 25-35 ℃ for 24 hours +/-10 minutes, continuously separating out generated water, washing and drying after the reaction is finished, dripping into diethyl ether for crystallization to obtain a crude product of the impurity V, and recrystallizing the crude product by methyl tert-butyl ether to obtain the purified product of the cis-atracurium besilate impurity V.
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