A kind of preparation method of rocuronium bromide intermediate

Abstract

The invention belongs to the technical field of drug synthesis, in particular to a preparation method of a rocuronium bromide intermediate. The preparation method takes the epiandrosterone shown in formula I as a raw material, carries out a dehydration reaction under the catalysis of Eaton reagent, and then obtains a rocuronium bromide intermediate (5α-androst-2-ene-17- after washing, extraction and concentration) ketone). The preparation method reduces the reaction temperature to 40°C, reduces the by-products of the high-temperature reaction, and the reaction solution can be simply washed with water, extracted, and concentrated to obtain an off-white solid, which reduces the loss of the main product caused by the removal of by-products by recrystallization. . The process is simpler, the yield is lower, and the discharge of three wastes is less.

Description

technical field

[0001] The invention belongs to the technical field of drug synthesis, in particular to a preparation method of a rocuronium bromide intermediate. Background technique

[0002] 5α-androst-2-en-17-one is an important intermediate for the synthesis of non-depolarizing steroidal muscle relaxants such as pancuronium, rocuronium, vecuronium, and pipecuronium. Sterol ammonium bromide drugs including rocuronium bromide and vecuronium bromide are a new type of non-depolarizing muscle relaxants that have appeared in recent years. They are used as anesthesia adjuncts for endotracheal intubation and surgery. Muscle relaxation has the characteristics of fast onset, short duration, no accumulation, no tachycardia and blood pressure changes, and no histamine release. Most of the existing commonly used methods for preparing 5α-androst-2-en-17-one use epiandrostone as a raw material, and are prepared by a two-step sulfonylation / elimination method.

[0003] Existing Chinese...

Examples

Embodiment 1

[0030] Add 15.6g (0.11mol) of phosphorus pentoxide and methanesulfonic acid (156g) to a clean 250mL three-necked flask, stir at room temperature for 2 hours, then add epiandrosterone (29.0g, 0.10mol), heat up to 110°C, and react At 6 hours, TLC showed no starting material. The reaction solution was lowered to room temperature, poured into 500 mL of water, extracted with 500 mL of dichloromethane, the organic phase was washed twice with 250 mL of 5% aqueous sodium carbonate solution, and the organic phase was washed twice with 250 mL of purified water, dried over anhydrous sodium sulfate, filtered, The dichloromethane was recovered by concentration under reduced pressure to obtain a dark brown oily substance, which was crystallized with methanol to obtain 21.6 g of off-white solids. The HPLC purity was greater than 95% and the molar yield was 79.4%. The detection chromatographic results were shown in Table 1 below. figure 1 shown.

[0031] Table 1 HPLC data table of purity of ...

Embodiment 2

[0035] Add 15.6g (0.11mol) of phosphorus pentoxide and methanesulfonic acid (156g) into a clean 250mL three-necked flask, stir at room temperature for 2 hours, then add epiandrosterone (29.0g, 0.10mol), heat up to 40°C, and react At 17 hours, TLC showed no starting material. The reaction solution was lowered to room temperature, poured into 500 mL of water, extracted with 500 mL of dichloromethane, the organic phase was washed twice with 250 mL of 5% aqueous sodium carbonate solution, and the organic phase was washed twice with 250 mL of purified water, dried over anhydrous sodium sulfate, filtered, The dichloromethane was recovered by concentration under reduced pressure to obtain 24.3 g of off-white solid with HPLC purity of 96.7% and molar yield of 89.3%. The detection chromatographic results are shown in Table 2 below. The chromatogram is shown in figure 2 shown.

[0036] Table 2 HPLC data table of purity of 5α-androst-2-en-17-one prepared in Example 2

[0037]

Embodiment 3

[0039] Phosphorus pentoxide (15.6g, 0.11mol), methanesulfonic acid (15.6g, 0.16mol), and dichloromethane (300mL) were added to a clean 500mL single-neck flask, stirred at room temperature for 2 hours, and then added epiandrosterone (29.0 g, 0.10 mol), the reaction was refluxed for 17 hours. The reaction solution was lowered to room temperature, poured into 500 mL of water, supplemented with 200 mL of dichloromethane, the organic phase was washed twice with 250 mL of 5% aqueous sodium carbonate solution, and the organic phase was washed twice with 250 mL of purified water, dried over anhydrous sodium sulfate, and filtered. , and concentrated under reduced pressure to recover dichloromethane to obtain 24.6 g of an off-white solid with a molar yield of 90.4%, a HPLC purity of 97.1%, and a moisture content of less than 0.1%. Its detection chromatographic results are shown in Table 3 below, and the chromatogram is shown in Table 3 below. image 3 shown.

[0040] Table 3 HPLC data...

technical field

[0001] The invention belongs to the technical field of drug synthesis, in particular to a preparation method of a rocuronium bromide intermediate. Background technique

[0002] 5α-androst-2-en-17-one is an important intermediate for the synthesis of non-depolarizing steroidal muscle relaxants such as pancuronium, rocuronium, vecuronium, and pipecuronium. Sterol ammonium bromide drugs including rocuronium bromide and vecuronium bromide are a new type of non-depolarizing muscle relaxants that have appeared in recent years. They are used as anesthesia adjuncts for endotracheal intubation and surgery. Muscle relaxation has the characteristics of fast onset, short duration, no accumulation, no tachycardia and blood pressure changes, and no histamine release. Most of the existing commonly used methods for preparing 5α-androst-2-en-17-one use epiandrostone as a raw material, and are prepared by a two-step sulfonylation / elimination method.

[0003] Existing Chinese...

Examples

Embodiment 1

[0030] Add 15.6g (0.11mol) of phosphorus pentoxide and methanesulfonic acid (156g) to a clean 250mL three-necked flask, stir at room temperature for 2 hours, then add epiandrosterone (29.0g, 0.10mol), heat up to 110°C, and react At 6 hours, TLC showed no starting material. The reaction solution was lowered to room temperature, poured into 500 mL of water, extracted with 500 mL of dichloromethane, the organic phase was washed twice with 250 mL of 5% aqueous sodium carbonate solution, and the organic phase was washed twice with 250 mL of purified water, dried over anhydrous sodium sulfate, filtered, The dichloromethane was recovered by concentration under reduced pressure to obtain a dark brown oily substance, which was crystallized with methanol to obtain 21.6 g of off-white solids. The HPLC purity was greater than 95% and the molar yield was 79.4%. The detection chromatographic results were shown in Table 1 below. figure 1 shown.

[0031] Table 1 HPLC data table of purity of ...

Embodiment 2

[0035] Add 15.6g (0.11mol) of phosphorus pentoxide and methanesulfonic acid (156g) into a clean 250mL three-necked flask, stir at room temperature for 2 hours, then add epiandrosterone (29.0g, 0.10mol), heat up to 40°C, and react At 17 hours, TLC showed no starting material. The reaction solution was lowered to room temperature, poured into 500 mL of water, extracted with 500 mL of dichloromethane, the organic phase was washed twice with 250 mL of 5% aqueous sodium carbonate solution, and the organic phase was washed twice with 250 mL of purified water, dried over anhydrous sodium sulfate, filtered, The dichloromethane was recovered by concentration under reduced pressure to obtain 24.3 g of off-white solid with HPLC purity of 96.7% and molar yield of 89.3%. The detection chromatographic results are shown in Table 2 below. The chromatogram is shown in figure 2 shown.

[0036] Table 2 HPLC data table of purity of 5α-androst-2-en-17-one prepared in Example 2

[0037]

Embodiment 3

[0039] Phosphorus pentoxide (15.6g, 0.11mol), methanesulfonic acid (15.6g, 0.16mol), and dichloromethane (300mL) were added to a clean 500mL single-neck flask, stirred at room temperature for 2 hours, and then added epiandrosterone (29.0 g, 0.10 mol), the reaction was refluxed for 17 hours. The reaction solution was lowered to room temperature, poured into 500 mL of water, supplemented with 200 mL of dichloromethane, the organic phase was washed twice with 250 mL of 5% aqueous sodium carbonate solution, and the organic phase was washed twice with 250 mL of purified water, dried over anhydrous sodium sulfate, and filtered. , and concentrated under reduced pressure to recover dichloromethane to obtain 24.6 g of an off-white solid with a molar yield of 90.4%, a HPLC purity of 97.1%, and a moisture content of less than 0.1%. Its detection chromatographic results are shown in Table 3 below, and the chromatogram is shown in Table 3 below. image 3 shown.

[0040] Table 3 HPLC data...

Images