Preparation method of rocuronium bromide intermediate 5 alpha-androstane-2-ene-17 ketone

Abstract

The invention relates to an industrial preparation method of an intermediate 5alpha-androstane-2-ene-17 ketone, the intermediate is a rocuronium bromide intermediate, and the method comprises the following steps: taking epiandrosterone as a starting material, and reacting with paratoluensulfonyl chloride to obtain a compound I; and carrying out elimination reaction on the compound I in organic alkali or a DBU catalyst to obtain the compound 5 alpha-androstane-2-ene-17 ketone. The method is good in elimination reaction selectivity, high in yield, good in quality, low in cost, mild in reaction condition, short in production period, recyclable in reaction solvent and green and environment-friendly in production process, and a single impurity of the product is less than 0.3%.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry, and particularly relates to an industrial preparation method of a rocuronium intermediate 5α-androst-2-ene-17-one. Background Art

[0002] The chemical structure formula of the 5α-androst-2-ene-17-one compound is as follows: .

[0003] The compound 5α-androst-2-ene-17-one is a key intermediate for the preparation of drugs such as rocuronium and vecuronium. Bromonium drugs are muscle relaxant drugs, which have a fast onset, good efficacy, and few side effects. They are mainly used for endotracheal intubation, intraoperative maintenance of muscle relaxation, anesthesia, ICU, and the treatment of spastic diseases.

[0004] Currently, the main synthetic routes for synthesizing this compound (hereinafter also referred to as the "target compound" in this article) are as follows:

[0005] Patents CN113637043A, CN103360455A, CN109678918A, CN109651473A, etc. have reported the preparation methods of 5α-androst-2-ene-17-one. However, these methods each have different defects and are not conducive to industrial production.

[0006] The methods disclosed in CN113637043A and CN103360455A use epiandrosterone as the starting material, react with p-dodecylbenzenesulfonyl chloride or p-toluenesulfonyl chloride to obtain a 3-position hydroxybenzene sulfonylation product, and use a monomethylpyridine solvent for high-temperature elimination reaction to obtain the target product. This preparation method has a long reaction time, incomplete raw material reaction, which affects the quality of downstream products. Moreover, the monomethylpyridine solvent has a strong odor and poor environmental friendliness. The generated by-product monomethylpyridine salt has a cyclic structure and is difficult to degrade and biochemically treat, causing great difficulties in sewage treatment. The post-treatment requires the use of 1% dilute sulfuric acid to adjust the pH, which has strong corrosiveness and is not conducive to industrial production.

[0007] The method disclosed in CN109651473A uses 4-androstene-dione as the raw material, undergoes etherification reaction, catalytic hydrogenation, acid-catalyzed hydrolysis to obtain epiandrosterone, and then uses solid-phase catalysis for elimination reaction to obtain the target compound. This method has a long synthetic route, involves a hazardous chemical process of hydrogenation reaction, the process of preparing solid catalysts is complex, the product needs to be refined multiple times, and the refined product is about 97-98.5%, and the product purity is poor.

[0008] The method disclosed in CN109678918A uses epiandrosterone as a raw material and dehydrates it under the catalysis of protonic acid and triflate to obtain the target product. The method uses toxic triflate, and triflate may extend toxic impurities, and the side reaction during the elimination reaction is large, the impurities are large, and the impurities are difficult to purify and control the quality, the synthesis yield is low, the reaction time is long, and it is not conducive to industrial implementation.

[0009] There are also foreign literature reports using silica gel adsorbed with p-toluenesulfonic acid as a catalyst. After adsorption at a mass ratio of m (silica gel): m (p-toluenesulfonic acid) of 100:7, the mixture was refluxed in toluene for 6 hours and recrystallized in methanol to obtain 5α-androst-2-ene-17-one with a purity of 98.9% at a high yield of 92.3%. This method uses too much silica gel, and the activity of the catalyst is greatly affected by the process. Too much solid waste is generated in production, and there are many factors affecting quality. The reproducibility is poor and it is not suitable for production.

[0010] The method disclosed in CN101684139A comprises the following steps: performing an esterification reaction between epiandrosterone and p-toluenesulfonyl chloride to generate epiandrosterone sulfonyl ester; performing a reflux reaction with 2,6-dimethylpyridine and 2,4,6-trimethylpyridine under the action of dilute sulfuric acid to perform an elimination reaction to generate 5α-androst-2-ene-17-one; the reaction uses 2,6-dimethylpyridine, 2,4,6-trimethylpyridine and other foul-smelling and toxic irritating substances, the reflux reaction temperature is relatively high, and general industrial conditions are difficult to achieve, and due to the high temperature, more impurities are generated, and post-treatment needs to be washed with 10% dilute sulfuric acid, which is highly corrosive, and has high cost and low yield. The yield of the reactant is only 80%, and the product quality purity is not reported, making industrial implementation difficult.

[0011] Based on the above-mentioned prior art, the existing preparation methods of 5α-androst-2-ene-17-one mostly use highly toxic, odorous and irritating substances, are highly corrosive, have poor environmental friendliness, are cumbersome to operate, have complex post-processing, are costly, have poor quality, have many method defects, and are difficult to implement industrially. Therefore, it is very necessary to develop a preparation method of 5α-androst-2-ene-17-one that is more conducive to industrial implementation. Summary of the invention

[0012] The object of the present invention is to provide an industrial preparation method of 5α-androst-2-ene-17-one, an intermediate of rocuronium bromide. The method overcomes the shortcomings of the prior art and has the advantages of being safe, effective, simple to operate, high product yield, product purity greater than 99%, a small number of product impurities, a single impurity less than 0.3%, a green process and environmental protection, and is more suitable for industrial production.

[0013] To achieve the purpose of the present invention, the following technical solutions are provided.

[0014] In an embodiment, a method for preparing a rocuronium intermediate 5α-androst-2-en-17-one (i.e., the target compound) of the present invention is characterized by comprising the following steps:

[0015] (1) Reacting epiandrosterone with p-toluenesulfonyl chloride in the presence of a catalyst to form Compound I; (2) Mixing Compound I with an organic base and reacting at a temperature of 100-150 °C for 2-10 hours to remove the protection to obtain the target compound, wherein the organic base solvent is tetramethylguanidine or N,N-diisopropylethylamine.

[0016] Preferably, in the above preparation method of the present invention, further comprising adding a catalyst DBU in step (2). Adding this catalyst can further shorten the reaction time and improve production efficiency.

[0017] Preferably, in the above preparation method of the present invention, the mass ratio of Compound I to the catalyst DBU is 1:0.1-1:1, more preferably 1:0.3-1:0.5.

[0018] Preferably, in the above preparation method of the present invention, in step (2), the mass ratio of Compound I to the organic base is 1:1-1:5, more preferably 1:1-1:2.

[0019] Preferably, in the above preparation method of the present invention, the temperature in step (2) is 125-145 °C.

[0020] Preferably, in the above preparation method of the present invention, the reaction time in step (2) is 3-6 hours.

[0021] Preferably, in the above preparation method of the present invention, the catalyst in step (1) is 4-dimethylaminopyridine.

[0022] In a specific embodiment, a method for preparing a rocuronium intermediate 5α-androst-2-en-17-one (i.e., the target compound) of the present invention is characterized by comprising the following steps:

[0023] (1) Reacting epiandrosterone with p-toluenesulfonyl chloride in the presence of a catalyst to form Compound I; (2) Mixing Compound I with the organic base tetramethylguanidine or / and N,N-diisopropylethylamine and reacting at a temperature of 125-145 °C for 3-6 hours to remove the protection to obtain the target compound, wherein the mass ratio of Compound I to the organic base is 1:1-1:2.

[0024] Further, in step 2), the catalyst 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) is added, and its dosage, the mass ratio of DBU to compound I is (0.3 - 0.5):1.

[0025] Step 1) is prepared with reference to the existing method, and the preferred catalyst is 4-dimethylaminopyridine.

[0026] In the preparation method of the present invention described above, in step 2), the organic bases tetramethylguanidine and N,N-diisopropylethylamine can be used alone or in combination as the solvent.

[0027] Technical effects of the preparation method of the present invention: The method of the present invention has good elimination reaction selectivity, high yield, high purity, and the individual impurities of the product are less than 0.3%. The reaction conditions are mild and the reaction time is short. The reaction solvent can be recycled and reused, and the production process is green and environmentally friendly. The raw materials and reagents are cheap and easily available, toxic materials are eliminated, the post-treatment is simple, the production cycle is short, the production cost of 5α-androst-2-ene-17-one can be greatly reduced, and it meets the requirements of industrial production. Description of the Drawings

[0028] Figure 1 It is the HPLC chart of the target compound prepared in Example 2; Figure 2 It is the HPLC chart of the target compound prepared in Example 3; Figure 3 It is the HPLC chart of the target compound prepared in Example 4; Figure 4 It is the HPLC chart of the target compound prepared in Example 5; Figure 5 It is the HPLC chart of the target compound prepared in Example 6; Figure 6 It is the HPLC chart of the target compound prepared in Example 7. Detailed Embodiments

[0029] The following examples are only representative and are used to further illustrate and understand the spiritual essence of the present invention, but do not limit the scope of the present invention.

[0030] The percentages involved in the examples are weight percentages, and the purity is determined by HPLC method (a chromatographic column with octadecylsilane-bonded silica gel as the filler (4.6×150mm, 3um); a differential refractive index detector; a flow rate of 1.3 ml / min; a column temperature of 30°C; an injection volume: 20 μl; a mobile phase composed of 35% water, 10% methanol, and 55% acetonitrile by volume percentage; an elution time of 65 min)

[0031] Preparation of Epitestosterone Tosylate (Compound I) Add 960.0 g of dichloromethane, 148.0 g of triethylamine, 200.0 g of epitestosterone, and 20.0 g of 4-dimethylaminopyridine to a 2000 mL three-necked flask. After adding, cool the temperature to 0 - 5 °C, and then add p-toluenesulfonyl chloride in batches, controlling the temperature within 0 - 20 °C. After adding, raise the temperature to 35 - 40 °C and react for 9 - 10 hours. After the reaction is completed, add 1000.0 g of drinking water and stir, then separate the layers. The aqueous layer is extracted once with 200.0 g of dichloromethane, and the dichloromethane organic layers are combined. The combined dichloromethane layer is distilled at atmospheric pressure (40 °C - 45 °C) until there is basically no dichloromethane distillate, and then vacuum concentration is carried out. After the concentration is completed, add 1000 ml of 50% ethanol solvent for slurrying, filter to obtain a white solid. The solid is dried under reduced pressure at a temperature of 50 - 60 °C and a vacuum degree of ≤ -0.08 Mpa for 22 - 24 h to obtain 300.0 - 306.1 g of dry product of Compound I, with a yield of 98.0% - 100.0% and a product purity greater than 99.0%.

[0032] Preparation of 5α-Androst-2-ene-17-one Add 150.0 g of Compound I and 150.0 g of tetramethylguanidine to a 1000 mL three-necked flask. After adding, start stirring and heat the oil bath to 135 °C. Control the reaction temperature at 135 ± 3 °C and react for 5 hours, then carry out vacuum distillation until dry; when the internal temperature drops to 80 - 90 °C, add 60 g of ethanol, stir to dissolve, when the internal temperature drops to 60 - 70 °C, add 900 g of hot water dropwise. Filter, wash the filter cake with a large amount of water and then with 50% ethanol to obtain the wet product of the target compound. Place the wet product of the target compound in an oven, set the temperature at 60 °C and the vacuum degree at ≤ -0.08 Mpa, and dry under reduced pressure for 22 - 24 h to obtain 87.3 g of dry product of the target compound, with a yield of 95.0%, a purity of 99.39%, unreacted raw materials of 0.19%, and individual impurities less than 0.3%, as Figure 1 shown.

[0033] Preparation of 5α-Androst-2-ene-17-one Add 150.0 g of Compound I, 150.0 g of N,N - diisopropylethylamine, and 45.4 g of DBU to a 1000 mL three - necked flask. After addition, start stirring and heat the oil bath to 135 °C. Control the reaction temperature at 135 ± 3 °C and react for 4 hours. Then perform vacuum distillation until dry. When the internal temperature drops to 80 - 90 °C, add 60 g of ethanol and stir to dissolve. When the internal temperature drops to 60 - 70 °C, add 900 g of hot water dropwise. Filter, wash the filter cake with a large amount of water and then with 50% ethanol to obtain the wet product of the target compound. Place the wet product of the target compound in an oven, set the temperature to 60 °C, the vacuum degree ≤ - 0.08 Mpa, and perform vacuum drying for 22 - 24 h to obtain 87.9 g of the dry product, with a yield of 95.6%, a purity of 99.95%, and individual impurities less than 0.3%, as Figure 2 shown.

[0034] Example 4 Preparation of 5α - androst - 2 - en - 17 - one Add 150.0 g of Compound I, 300.0 g of tetramethylguanidine, and 40.0 g of DBU to a 1000 mL three - necked flask. After addition, start stirring and heat the oil bath to 140 °C. Control the reaction temperature at 140 ± 3 °C and react for 3 hours. Then perform vacuum distillation until dry. When the internal temperature drops to 80 - 90 °C, add 60 g of ethanol and stir to dissolve. When the internal temperature drops to 60 - 70 °C, add 900 g of hot water dropwise. Filter, wash the filter cake with a large amount of water and then with 50% ethanol to obtain the wet product of the target compound. Place the wet product of the target compound in an oven, set the temperature to 60 °C, the vacuum degree ≤ - 0.08 Mpa, and perform vacuum drying for 22 - 24 h to obtain 87.2 g of the dry product, with a yield of 94.9%, a purity of 99.57%, and individual impurities less than 0.3%, as Figure 3 shown.

[0035] Example 5 Preparation of 5α - androst - 2 - en - 17 - one Add 150.0 g of Compound I and 300.0 g of N,N - diisopropylethylamine to a 1000 mL three - necked flask. After addition, start stirring and heat the oil bath to 130 °C. Control the reaction temperature at 130 ± 3 °C and react for 6 hours. Then perform vacuum distillation until dry. When the internal temperature drops to 80 - 90 °C, add 60 g of ethanol and stir to dissolve. When the internal temperature drops to 60 - 70 °C, add 900 g of hot water dropwise. Filter, wash the filter cake with a large amount of water and then with 50% ethanol to obtain the wet product of the target compound. Place the wet product of the target compound in an oven, set the temperature to 60 °C, the vacuum degree ≤ - 0.08 Mpa, and perform vacuum drying for 12 - 14 h to obtain 86.7 g of the dry product, with a yield of 94.3%, a purity of 99.51%, as Figure 4 shown.

[0036] Example 6 Preparation of 5α - androst - 2 - en - 17 - one Add 60.0 kg of Compound I and 120.0 kg of N,N-diisopropylethylamine to a 1000 L reactor. After addition, start stirring and heat up to 130 °C. Control the reaction temperature at 130 ± 3 °C for 6 hours, then carry out vacuum distillation until dry. When the internal temperature drops to 80 - 90 °C, add 24 kg of ethanol, stir to dissolve, and when the internal temperature drops to 60 - 70 °C, add 360.0 kg of hot water dropwise. Filter, wash the filter cake with a large amount of water and then with 50% ethanol to obtain the wet product of the target compound. Place the wet product of the target compound in an oven, set the temperature at 60 °C, the vacuum degree ≤ -0.08 Mpa, and carry out vacuum drying for 12 - 14 h to obtain 34.8 kg of dry product, with a yield of 94.66% and a purity of 100.0%, as Figure 5 shown.

[0037] The inventor of the present invention carried out a reaction comparison experiment according to the monomethylpyridine solvent in CN103360455A, stopped the reaction according to the reaction time, and found that the unreacted raw materials were more than 3.0%.

[0038] Comparative Example 1 Preparation of 15α-androst-2-en-17-one Add 150.0 g of Compound I and 300.0 g of 2-methylpyridine to a 1000 mL three-necked flask. After addition, start stirring and heat up to 130 °C in an oil bath. Control the reaction temperature at 130 ± 3 °C for 6 hours, then carry out vacuum distillation until dry. When the internal temperature drops to 80 - 90 °C, add 60 g of ethanol, stir to dissolve, and when the internal temperature drops to 60 - 70 °C, add 900 g of hot water dropwise. Filter, wash the filter cake with a large amount of water and then with 50% ethanol to obtain the wet product of the target compound. Place the wet product of the target compound in an oven, set the temperature at 60 °C, the vacuum degree ≤ -0.08 Mpa, and carry out vacuum drying for 22 - 24 h to obtain 76.2 g of dry product, with a yield of 82.9% and a purity of 89.45%, and the unreacted raw material Compound I is 4.73%, as Figure 6 shown.

[0039] The above embodiments are typical. Any simple modification or variation based on the spirit and essence of the present invention also falls within the protection scope of the present invention.

Claims

1. A preparation method of rocuronium intermediate 5α-androst-2-ene-17-one, characterized in that, It includes the following steps: 1) Reacting epiandrosterone with p-toluenesulfonyl chloride in the presence of a catalyst to form Compound I; 2) Mixing Compound I with an organic base solvent and reacting at a temperature of 100 - 150 °C for 2 - 10 hours to deprotect and obtain the target compound, wherein the organic base solvent is tetramethylguanidine or N,N-diisopropylethylamine.

2. The preparation method according to claim 1, further comprising adding the catalyst DBU in step 2).

3. The preparation method according to claim 2, wherein the mass ratio of Compound I to the catalyst DBU is 1:0.1 - 1:

1.

4. The preparation method according to claim 3, wherein the mass ratio of Compound I to the catalyst DBU is 1:0.3 - 1:0.

5.

5. The preparation method according to claim 1, in step 2), the mass ratio of Compound I to the organic base is 1:1 - 1:

5.

6. The preparation method according to claim 5, wherein the mass ratio of Compound I to the organic base is 1:1 - 1:

2.

7. The preparation method according to claim 1, in step 2), the temperature is 125 - 145 °C.

8. The preparation method according to claim 1, in step 2), the reaction time is 3 - 6 hours.

9. The preparation method according to claim 1, in step 1), the catalyst is 4-dimethylaminopyridine.

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