Cisatracurium besilate process impurity and synthesis method thereof

Abstract

The invention relates to a cisatracurium besilate process impurity and a synthesis method thereof. The structure of the cisatracurium besilate process impurity is shown as a formula I in the specification. The synthesis method comprises the following steps: 1) adding (1R, 2R)-1, 2, 3, 4-tetrahydro-6, 7-dimethoxy-2-[2-(t-butyloxycarbonyl) ethyl]-2-methyl-1-veratryl isoquinolinium benzene sulfonate into acetonitrile, and adding tert-butyl hydroperoxide to obtain an intermediate A; 2) adding the intermediate A into 70% benzenesulfonic acid, and hydrolyzing to obtain an intermediate B; and 3) adding the intermediate B and (1R, 2R)-1, 2, 3, 4-tetrahydro-6, 7-dimethoxy-2-(9-hydroxy-3-oxo-4-oxynonyl)-2-methyl-1-veratryl isoquinolinium benzene sulfonate into dichloromethane, carrying out reflux, after the reaction is finished, carrying out washing and drying, and carrying out preparation and separation to obtain the cisatracurium besylate process impurity. The impurity can be used as a reference substance for detecting cisatracurium besilate related substances, and is used for controlling the purity of a cisatracurium besilate bulk drug.

Description

Technical Field

[0001] The present invention relates to the field of chemical synthesis, and particularly to a process impurity of cisatracurium besilate and its synthesis method. Background Art

[0002] Cisatracurium Besilate is a neuromuscular blocker developed by GlaxoSmithKline. It was first marketed in the UK in 1996 and has gradually replaced vecuronium and atracurium abroad and become the mainstream of clinical muscle relaxants.

[0003] Cisatracurium Besilate is a medium-acting, non-depolarizing skeletal muscle relaxant with an isoquinolinium benzyl ester structure. Cisatracurium Besilate binds to cholinergic receptors at the motor end plate to antagonize the action of acetylcholine, thereby producing a competitive neuromuscular conduction block. This effect can be easily antagonized by anticholinesterase drugs such as neostigmine or edrophonium chloride. Compared with the current main clinical muscle relaxant anesthetics, cisatracurium besilate has the characteristics of metabolism through non-hepatic and non-renal pathways and cardiovascular stability. Its muscle relaxant effect is 3 times stronger than that of atracurium and it has no cardiovascular side effects. Cisatracurium Besilate is mainly applicable to general anesthesia and can be widely used in tracheal intubation, patients with liver and kidney dysfunction, cardiovascular surgery, as well as elderly and pediatric patients. Its structure is shown in Formula II:

[0004]

[0005] Currently, the synthesis of cisatracurium besilate mainly uses (R)-1,2,3,4-tetrahydropapaverine as the starting material (WO2008132748), and cisatracurium besilate is obtained through addition, quaternization, resolution, hydrolysis, and esterification.

[0006] During the detection of cisatracurium besilate, it was found that there is a related impurity whose structure has not been disclosed in the existing literature. It is present in multiple batches at about 0.02 - 0.04% and, as an unknown impurity with a relatively high content, it is necessary to confirm the structure of this impurity and at the same time provide a preparation method for this impurity.

[0007] Through research, the inventors of the present invention have confirmed the structure of the impurity of cisatracurium besilate and provided a synthesis method. The method is simple to operate and has high purity, providing high-purity impurity samples and reference standards for the process research and quality control of cisatracurium besilate. Summary of the Invention

[0008] The present invention provides a process impurity of cisatracurium besilate and its synthesis method.

[0009] The process impurity of cisatracurium besylate provided by the present invention has the chemical name: (1R,2S)-2-(3,11-dioxo-4,10-dioxa-13-((1R,2R)-1,2,3,4-tetrahydro-6,7-dimethoxy-2-methyl-1-veratrylisoquinolinium-2-yl)tridecyl)-1,2,3,4-tetrahydro-6,7-dimethoxy-2-methyl-1-veratryl-4-oxoisoquinolinium dibenzenesulfonate (hereinafter referred to as impurity M), and its chemical structural formula is as follows:

[0010]

[0011] Comparing its structure, one of the benzyl methylene groups of cisatracurium besylate is oxidized to a carbonyl group. It is similar in structure to cisatracurium besylate and is difficult to separate. The existing pharmacopoeia methods have no separation effect on this impurity and are easily overlooked. To ensure the product quality of cisatracurium besylate, it is necessary to control this impurity.

[0012] The synthesis method described in the present invention has the following synthetic route:

[0013]

[0014] The technical effects of the present invention are:

[0015] The present invention confirmed the specific structure of impurity M through the nuclear magnetic resonance hydrogen spectrum, carbon spectrum and mass spectrum of the compound, and separated it from cisatracurium besylate by high performance liquid chromatography, providing a solid foundation for the research on the process impurities of cisatracurium besylate. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Appendix Figure 1 : Detection spectrum

[0017] Appendix Figure 2 : Nuclear magnetic resonance hydrogen spectrum

[0018] Appendix Figure 3 : Nuclear magnetic resonance carbon spectrum

[0019] Appendix Figure 4 : Mass spectrum DETAILED DESCRIPTION OF THE INVENTION

[0020] The following examples are for further illustrating the present invention and do not constitute any limitation to the present invention.

[0021] Example: A method for preparing (1R,2S)-2-(3,11-dioxo-4,10-dioxo-13-((1R,2R)-1,2,3,4-tetrahydro-6,7-dimethoxy-2-methyl-1-veratrylisoquinolinium-2-yl)tridecyl)-1,2,3,4-tetrahydro-6,7-dimethoxy-2-methyl-1-veratryl-4-oxoisoquinolinium dibenzenesulfonate.

[0022] Step 1: In a 250 mL single-necked flask, add 5.00 g of (1R,2R)-1,2,3,4-tetrahydro-6,7-dimethoxy-2-[2-(tert-butoxycarbonyl)ethyl]-2-methyl-1-veratrylisoquinolinium benzenesulfonate, 50 mL of acetonitrile, and 1.03 g of manganese dioxide. Stir evenly, add 3.5 mL of tert-butyl hydroperoxide in batches, stir and react at 70 °C for 11 days. Filter the system, concentrate the filtrate, dissolve the residue in 10 mL of dichloromethane, add 50 mL of ether, stir and crystallize, discard the supernatant, and vacuum dry the residue at ambient temperature to obtain 0.71 g of yellow foamy solid intermediate A.

[0023] Step 2: Add 0.50 g of intermediate A to a 50 mL single-necked flask, add 0.5 mL of 70% benzenesulfonic acid, and react under reduced pressure in a 55 °C water bath for 2 hours.

[0024] Step 3: Add 0.61 g of (1R,2R)-1,2,3,4-tetrahydro-6,7-dimethoxy-2-(9-hydroxy-3-oxo-4-oxononyl)-2-methyl-1-veratrylisoquinolinium benzenesulfonate and 20 mL of dichloromethane. After refluxing the system for 7 hours, cool it down, wash the solution with benzenesulfonic acid solution. After the washing is completed, add 30 mL of methyl tert-butyl ether to the organic phase and stir to crystallize. Discard the supernatant, and vacuum dry the residue at 30 °C to obtain 0.42 g of crude product. Separate it by HPLC preparation to obtain 96 mg of brown solid impurity M with an HPLC content of 92.6%.

[0025] The above-disclosed are only the preferred embodiments of the present invention, and the scope of the rights of the present invention cannot be limited thereby. Therefore, equivalent changes made according to the claims of the present invention still fall within the scope covered by the present invention.

Claims

1. An impurity of cisatracurium besylate, with the chemical name: (1R,2S)-2-(3,11-dioxo-4,10-dioxo-13-((1R,2R)-1,2,3,4-tetrahydro-6,7-dimethoxy-2-methyl-1-veratrylisoquinolinium-2-yl)tridecyl)-1,2,3,4-tetrahydro-6,7-dimethoxy-2-methyl-1-veratryl-4-oxoisoquinolinium dibenzenesulfonate, having the following structure:

2. A method for preparing the process impurity according to claim 1, characterized in that the reaction formula is as follows: including the following routes: a) Adding (1R,2R)-1,2,3,4-tetrahydro-6,7-dimethoxy-2-[2-(tert-butoxycarbonyl)ethyl]-2-methyl-1-veratrylisoquinolinium benzenesulfonate to acetonitrile, and adding tert-butyl hydroperoxide for oxidation to obtain intermediate A; b) Adding intermediate A to 70% benzenesulfonic acid for hydrolysis to obtain intermediate B; c) Adding intermediate B and (1R,2R)-1,2,3,4-tetrahydro-6,7-dimethoxy-2-(9-hydroxy-3-oxo-4-oxononyl)-2-methyl-1-veratrylisoquinolinium benzenesulfonate to dichloromethane for reflux. After the reaction is completed, after washing and drying, the cisatracurium besylate process impurity is prepared and separated.

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