Preparation method of rocuronium bromide key intermediate

Abstract

The invention discloses a preparation method of a rocuronium bromide key intermediate, and the preparation method comprises the following steps: taking 5alpha-androstane-2-ene-17-ketone as a raw material, and carrying out bromination, nucleophilic substitution and oxidation to obtain 2alpha, 3alpha-epoxy-16beta-(1-pyrrolyl)-5alpha-androstane-17-ketone; the preparation method has the advantages of cheap and easily available raw materials, simple operation, short preparation period, high purity and high yield, and can be used for industrial production of rocuronium bromide.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical intermediate preparation technology, specifically a method for preparing a key intermediate of rocuronium bromide. Background Technology

[0002] Rocuronium bromide, CAS number 119302-91-9, chemical name: 1-[17β-acetoxy-3α-hydroxy-2β-(4-morpholinyl)-5α-androstane-16β-yl]-1-(2-propenyl)pyrrolidine bromide, is a skeletal muscle relaxant, mainly used clinically for general anesthesia, skeletal muscle relaxation, and endotracheal intubation.

[0003] Gu Guangzhi et al. reported three methods for synthesizing rocuronium bromide. All three methods share a common key intermediate: 2α,3α-epoxy-16β-(1-pyrrolidinyl)-5α-androst-17-one, with the structural formula shown in Formula I. .

[0004] Currently reported methods for synthesizing 2α,3α-epoxy-16β-(1-pyrrolidinyl)-5α-androst-17-one include: 1) Patent document WO2007033348A2 discloses a method for preparing a product using 2α,3α,16α,17α-bisepoxy-5α-androstane-17β alcohol acetate as a raw material, which is obtained through ester hydrolysis and purification. The product contains isomers and requires further purification.

[0005] 2) It is prepared from 5α-androst-2-en-17-one as a raw material through a five-step reaction involving hydrazone, NBS bromination, oxidation, rearrangement, and pyrrolidine nucleophilic substitution. This process involves many reaction steps and uses explosive reagents, posing safety hazards.

[0006] 3) Patent document US5817803A discloses a five-step reaction process using epiandrolone as a raw material to prepare homologue I, as shown in formula II, through sulfonation, elimination, CuBr2 bromination, epoxidation, and N nucleophilic substitution. This process involves epoxidation followed by N nucleophilic substitution. In addition to attacking the bromine atom, N also attacks the epoxide, causing it to open the ring, as shown in formula III, resulting in low product purity. The specific route is as follows: ;

[0007] Therefore, it is necessary to propose a method for preparing the key intermediate of rocuronium bromide to solve the above problems. Summary of the Invention

[0008] This invention provides a method for preparing a key intermediate of rocuronium bromide, which at least solves one of the many defects of existing technologies, such as multiple isomers of reaction products, high safety risks, and low product purity.

[0009] In view of this, the solution of the present invention is as follows: A method for preparing a key intermediate of rocuronium bromide, comprising the following steps: S1,5α-androst-2-en-17-one, brominating agent and water under the action of an acidic catalyst to generate intermediate one; S2. Intermediate 1 reacts with tetrahydropyrrole in a polar aprotic solvent to generate intermediate 2; S3. Intermediate II reacts under the action of an oxidant to obtain a reaction solution containing the structure of formula I, which is then purified to obtain the pure product of the key intermediate of rocuronium bromide. The reaction route of the preparation method is as follows: .

[0010] Further, in step S1, the brominating agent is at least one of bromine, 1,3-dibromo-5,5-dimethylhydantoin, pyridine tribromide, and 5,5-dibromomelendronic acid; And / or, the acidic catalyst is selected from at least one of glacial acetic acid, sulfuric acid, or p-toluenesulfonic acid.

[0011] Further, in step S1, the molar ratio of the 5α-androst-2-en-17-one to the brominated reagent is 1:(0.2-1.5).

[0012] Furthermore, in step S1, the reaction temperature is 20-70℃ and the reaction time is 0.5-2h.

[0013] Furthermore, in step S2: The polar aprotic solvent is selected from at least one of dimethyl sulfoxide, dimethylformamide, acetone, acetonitrile, and tetrahydrofuran; And / or, the molar ratio of intermediate one to tetrahydropyrrole is 1:(3-8); And / or, the reaction temperature is 60-85℃ and the reaction time is 1-5h.

[0014] Furthermore, in step S3: The oxidant is selected from at least one of m-chloroperoxybenzoic acid, hydrogen peroxide, and potassium persulfate complex salt; And / or, the molar ratio of intermediate II to oxidant is 1:(0.8-1.5).

[0015] And / or, the oxidation reaction process is carried out at a temperature of 0-30℃ and for a reaction time of 5-10h.

[0016] Further, in step S3, the purification process involves extracting the reaction solution and collecting the organic phase, washing and drying the organic phase, concentrating it, adding alcohol and purified water to the concentrate in sequence, heating and refluxing, then cooling to crystallize, filtering and drying to obtain the pure product.

[0017] Preferably, the organic phase washing process uses one or more aqueous solutions of inorganic salts.

[0018] Preferably, the drying process involves adding a dehydrating agent to the washed organic phase, followed by filtration and collection of the filtrate.

[0019] Another object of the present invention is to provide a method for preparing rocuronium bromide, comprising preparing rocuronium bromide based on a compound intermediate of Formula I; wherein the compound intermediate of Formula I is obtained by the preparation method described above.

[0020] Compared with the prior art, the present invention has the following beneficial effects: The method for preparing the key intermediate of rocuronium bromide provided by this invention uses 5α-androst-2-en-17-one as a raw material, and obtains 2α,3α-epoxy-16β-(1-pyrrole)-5α-androst-17-one through bromination, nucleophilic substitution and oxidation. The preparation method uses inexpensive and readily available raw materials, is simple to operate, and has a short preparation cycle. The yield of intermediates or products obtained in each step is above 80%, and the purity of the final product is greater than 99%. It is suitable for the industrial production of rocuronium bromide. Detailed Implementation

[0021] The technical solution of the present invention will now be clearly and completely described in conjunction with preferred embodiments. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of them. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0022] Example 1

[0023] A method for preparing a key intermediate of rocuronium bromide, comprising the following steps: 1) Add 1.5 kg (5.506 mol) of 5α-androst-2-en-17-one, 4.5 kg of water, and 10 ml of glacial acetic acid to a 10 L glass reaction flask, and cool to 1 °C. Add 0.97 kg of bromine dropwise. After the addition is complete, react at 58 °C for 1 h, cool to 5 °C, filter, wash with 2 kg of water, and obtain 1.64 kg of solid intermediate, yield 84.8%, purity 98.2%.

[0024] 2) Add the above intermediate one solid, 4L of acetone and 1.17kg of tetrahydropyrrole to a 10L glass reaction flask, heat to 85℃ and react for 2h, cool to room temperature, and concentrate under reduced pressure at 45℃ to obtain 1.68kg of solid intermediate two, with a yield of 85.4% and a purity of 98.4%.

[0025] 3) Add 3L of the above solid intermediate di-tetrahydrofuran to a 20L glass reaction flask, and add 6L of tetrahydrofuran solution containing 1.14kg of 85% m-chloroperoxybenzoic acid. After the addition is complete, keep the mixture at 30℃ for 5h. Pour the reaction solution into 3L of saturated sodium bicarbonate solution, add 3L of ethyl acetate, separate the layers, collect the organic phase, and wash it successively with 1L of 5% sodium thiosulfate solution, 1L of 10% sodium bicarbonate solution, and 1.5L of 10% sodium chloride solution. Collect the organic layer, add 1kg of sodium sulfate to dry it, filter the solution, wash the filter cake with 0.8L of ethyl acetate, collect the filtrate, concentrate it under reduced pressure at 38℃, add 5kg of methanol to the residue, heat to reflux, and add 10kg of purified water dropwise under reflux. After adding the product dropwise, reflux for 30 minutes with stirring, cool to 5°C for 1 hour to allow crystals to precipitate, filter, wash the filter cake with 4 kg of water, dry at 50°C, and obtain 1.43 kg of pure product with structure I, yield 82.0% and purity 99.5%.

[0026] Example 2

[0027] A method for preparing a key intermediate of rocuronium bromide, comprising the following steps: 1) Add 1.5 kg of 5α-androst-2-en-17-one, 4.5 kg of water, 1 ml of sulfuric acid and 0.86 kg of DBH to a 10 L glass reaction flask. React at 23 °C for 1 h, cool to 3 °C, filter, wash with 2 kg of water to obtain 1.74 kg of solid intermediate, yield 90.0% and purity 98.5%.

[0028] 2) Add the above solid intermediate one, 2.5L of acetonitrile and 1.57kg of tetrahydropyrrole to a 10L glass reaction flask, heat to 81℃ and react for 3h, cool to room temperature, and concentrate under reduced pressure at 40℃ to obtain solid intermediate two 1.86kg, with a yield of 89.1% and a purity of 98.8%.

[0029] 3) Add 3L of the above solid intermediate dichloromethane to a 20L glass reaction flask, and add 0.54kg of 30% hydrogen peroxide dropwise. After the addition is complete, maintain the temperature at 2℃ for 8 hours. Add 3L of saturated sodium bicarbonate solution, separate the layers, collect the organic layer, add 1kg of sodium sulfate to dry, filter the solution, wash the filter cake with 0.8L of dichloromethane, collect the filtrate, concentrate under reduced pressure at 36℃, add 5kg of methanol to the residue, heat to reflux, and add 15kg of purified water dropwise under reflux. After the addition is complete, reflux for 30 minutes with stirring, cool to 1℃ to crystallize for 1 hour, filter, wash the filter cake with 4kg of water, and dry at 40℃ to obtain 1.55kg of pure product of formula I, with a yield of 80.3% and a purity of 99.1%.

[0030] Example 3

[0031] A method for preparing a key intermediate of rocuronium bromide, comprising the following steps: 1) Add 1.5 kg of 5α-androst-2-en-17-one, 4.5 kg of water, 1 ml of sulfuric acid and 0.86 kg of DBH to a 10 L glass reaction flask. React at 25 °C for 1 h, cool to 2 °C, filter, wash with 2 kg of water to obtain 1.74 kg of solid intermediate, yield 90.0% and purity 98.1%.

[0032] 2) Add the above solid intermediate one, 4L of acetone and 2.35kg of tetrahydropyrrole to a 10L glass reaction flask, heat to 65℃ and react for 4h, cool to room temperature, and concentrate under reduced pressure at 50℃ to obtain solid intermediate two 1.70kg, with a yield of 81.4% and a purity of 98.3%.

[0033] 3) Add 3L of the above solid intermediate di-tetrahydrofuran to a 20L glass reaction flask, and add 6L of a tetrahydrofuran solution containing 1.14kg of 85% m-chloroperoxybenzoic acid dropwise. After the addition is complete, keep the mixture at 20℃ for 5h. Pour the reaction solution into 3L of saturated sodium bicarbonate solution, add 3L of ethyl acetate, separate the layers, collect the organic phase, and wash it successively with 1L of 5% sodium thiosulfate solution, 1L of 10% sodium bicarbonate solution, and 1.5L of 10% sodium chloride solution. Collect the organic layer, add 1kg of sodium sulfate to dry it, filter the solution, wash the filter cake with 0.8L of ethyl acetate, collect the filtrate, concentrate it under reduced pressure at 37℃, add 5kg of methanol to the residue, heat to reflux, and add 15kg of purified water dropwise under reflux. After adding the product dropwise, reflux for 30 minutes with stirring, cool to 0-5℃ to crystallize for 1 hour, filter, wash the filter cake with 4 kg of water, dry at 42℃, and obtain 1.46 kg of pure product with structure I, yield 82.8%, purity 99.5%.

[0034] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A process for the preparation of a key intermediate of rocuronium bromide, characterized by the steps of The preparation method comprises the following steps: S1.5α-androst-2-ene-17-one, a brominating agent and water are reacted under the action of an acidic catalyst to obtain intermediate one; S2. Intermediate one is reacted with tetrahydropyrrole in a polar aprotic solvent to obtain intermediate two; S3. Intermediate two is reacted under the action of an oxidizing agent to obtain a reaction solution containing the structure of formula I, and the reaction solution is refined to obtain the pure product of the key intermediate of rocuronium bromide; The reaction route of the preparation method is as follows: 。 2. The production method according to claim 1, characterized by, In step S1, the brominating agent is at least one of bromine, 1,3-dibromo-5,5-dimethylhydantoin, pyridine tribromide and 5,5-dibromo-meldrum's acid. And / or, the acidic catalyst is at least one of glacial acetic acid, sulfuric acid or p-toluenesulfonic acid.

3. The preparation method according to claim 1, characterized in that, In step S1, the molar ratio of 5α-androst-2-ene-17-one to the brominating agent is 1: (0.2-1.5).

4. The production method according to claim 1, characterized by, In step S1, the reaction temperature is 20-70°C, and the reaction time is 0.5-2h.

5. The preparation method according to claim 1, characterized in that, In step S2: The polar aprotic solvent is at least one of dimethyl sulfoxide, dimethylformamide, acetone, acetonitrile and tetrahydrofuran; And / or, the molar ratio of intermediate one to tetrahydropyrrole is 1: (3-8); And / or, the reaction temperature is 60-85°C, and the reaction time is 1-5h.

6. The method of claim 1, wherein, In step S3, the oxidizing agent is at least one of meta-chloroperoxybenzoic acid, hydrogen peroxide and potassium peroxymonosulfate complex salt; And / or, the molar ratio of intermediate two to the oxidizing agent is 1: (0.8-1.5).

7. The preparation method according to claim 1, characterized in that, In step S3, the temperature during the oxidation reaction process is 0-30°C, and the reaction time is 5-10h.

8. The method of claim 1, wherein, In step S3, the refining process is as follows: the reaction solution is extracted, and the organic phase is collected; the organic phase is washed and dried, and then concentrated; alcohol and purified water are sequentially added to the concentrated solution and heated to reflux; then, the temperature is lowered to crystallize, and the filter cake is dried to obtain the pure product.

9. The production method according to claim 8, characterized by, One or more inorganic salt aqueous solutions are used in the washing process of the organic phase; And / or, the drying process is as follows: a dehydrating agent is added to the washed organic phase, and then the filtrate is collected by filtration.

10. A process for the preparation of rocuronium bromide, characterized in that, The application further provides a preparation method of rocuronium bromide based on a compound with the structure of formula I, wherein the compound with the structure of formula I is prepared by the preparation method of any one of claims 1-9.

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