KR101016608B1 - Method For Preparing Rocuronium Bromide - Google Patents

Abstract

A method for preparing a Rocuronium Bromide compound according to the present invention is a manufacturing method comprising the step of reacting a compound of Formula IV with morpholine, thereby preparing a high purity and high quality Locuronium bromide compound can do.

(IV)

(IV)

Rocuronium Bromide

Description

Method for preparing rocuronium bromide {Method For Preparing Rocuronium Bromide}

The present invention relates to a process for the preparation of high purity and high quality rocuronium bromide compounds.

Locuronium bromide is a 1-[(2β, 3α, 5α, 16β, 17β) -17- (acetyloxy) -3-hydroxy-2- (4-morpholinyl) androstane represented by the formula -16-yl] -1- (2-propenyl) pyrrolidium bromide and has been used as a non-depolarizing neuromuscular blocker.

(I)

(I)

In order to investigate the efficacy as an anesthetic, researches for synthesizing various derivatives through androstanes having the structure of Formula II have been conducted. In particular, 2β-morpholino-androstan derivatives have excellent effects as non-depolarizing neuromuscular blockers. It was confirmed that it can be represented.

(II)

(II)

In this regard, U.S. Patent Application Publication No. 4,894,369 reported for the first time a method for synthesizing rocuronium bromide, which is a compound of formula III, 2α, 3α-epoxy-16β- (1-pyrrolidinyl) -5α- A process for preparing rocuronium bromide via androstane-17β-ol is disclosed.

(III)

(III)

2β- (4-morpholinyl) -16β- (1 by reacting 2α, 3α-epoxy-16β- (1-pyrrolidinyl) -5α-androstan-17β-ol as a compound of Formula III with morpholine -Pyrrolidinyl) -5α-androstan-3α, 17β-diol was prepared, and an acylation reaction was performed to proceed with 2β- (4-morpholinyl) -16β- (1-pyrrolidinyl) -5α-androstane. A process for preparing -3α, 17β-diol-17 acetate to obtain locuronium bromide is disclosed.

However, the acetate compound produced through the reaction is shown to be obtained in a low yield of about 50%, the content is low, it has to go through a separate recrystallization step, the content of the resulting rocuronium bromide is impurity column chromatography on alumina There is a problem in that a process of performing purification and performing purification is essential. Therefore, the yield of the reaction is notably reduced, and the production time and production cost required for the preparation of rocuronium bromide are greatly increased, which is not industrially useful.

Accordingly, an object of the present invention is to solve the problems of the prior art as described above and the technical problems that have been requested from the past.

In particular, it is an object of the present invention to provide an industrially useful process for producing high purity and high quality rocuronium bromide.

The method for preparing rocuronium bromide according to the present invention for achieving this object comprises the step of reacting a compound of formula IV with morpholine.

(IV)

(IV)

The present invention also relates to 2α, 3α-epoxy-5α-androstan-17-one compounds of formula IV used for the preparation of rocuronium bromide.

The preparation method of rocuronium bromide according to the present invention is very useful industrially, and through this preparation method, high purity and high quality rocuronium bromide can be prepared.

A process for preparing rocuronium bromide according to the present invention is a process for preparing rocuronium bromide through the compound of the following formula (IV), which is a novel process that has not been reported so far.

(IV)

(IV)

Conventional International Patent Application No. 2007/033348 discloses rocuronium using 2α, 3α-epoxy-16β- (1-pyrrolidinyl) -5α-androstan-17-one in which a pyrrolidine group is introduced in Formula IV. Although a method for preparing bromide is disclosed, in contrast, the preparation method according to the present invention is prepared by preparing rocuronium bromide through a compound of formula IV, which is 2α, 3α-epoxy-5α-androstan-17-one, Compared to the preparation method of rocuronium bromide which introduces a lollidine group first, it is possible to remarkably suppress the formation of a flexible substance. When the preparation of locuronium bromide through such preparation method, high purity of about 99% or more is determined by HPLC analysis. And high quality rocuronium bromide. In this respect, the manufacturing method according to the present invention is very useful industrially, the reaction can be controlled in a gentle state, it can be said that the efficiency in the manufacturing process is also very excellent.

The preparation method is a step of reacting a compound of formula (IV) with morpholine, thereby obtaining a compound of formula (V).

(IV)

(IV)

(V)

(V)

The preparation method is carried out in the presence of a solvent prior to the reaction of the compound of formula IV with morpholine, 5α-androst-2-en-17-one, hydrogen peroxide or m-chloroperbenzoic acid (m- Reaction of chloroperbenzoic acid) may further comprise the step of obtaining a compound of formula (IV).

(IX)

(IX)

The compound of formula (IX) may be obtained by tosylation of alcohol and detoluenesulphonic acid reaction from epiandrosterone, as shown in Scheme 1 below.

Scheme 1

The solvent is not particularly limited, but may be, for example, an aprotic solvent or an inert solvent, and is a group consisting of tetrahydrofuran, chloroform, dichloromethane, diethyl ether, t-butyl dimethyl ether, ether, methylene chloride and carbon tetrachloride. It may be one or more selected from, and may be preferably ether. As in the following examples, it was confirmed that the most effective reaction when using m-chloroperbenzoic acid in ether solvent.

In one preferred embodiment, the hydrogen peroxide or m-chloroperbenzoic acid may be used in an amount of 1.0 to 1.2 equivalents (atomic weight / atom: eq). When the hydrogen peroxide or m-chloroperbenzoic acid is less than 1.0 equivalent, the reaction may not occur to the desired degree, and when more than 1.2 equivalent, a side reaction may proceed.

In one preferred embodiment, the reaction can proceed for 2 to 4 hours at a temperature of -5 to 10 ℃, preferably 3 hours at 5 ℃, the reaction temperature and time can be adjusted to the desired degree . However, if the reaction temperature is too high, the reaction time is shortened, but there is a fear that side reactions occur, and if the reaction temperature is too low, the reaction time may be long and may not be industrially effective.

In some cases, the compound of Formula IV-a may be produced as an unwanted impurity during the reaction, and may be generated at about 15-20 area% in HPLC analysis.

(IV-a)

(IV-a)

Thus, the Locuronium bromide compound may be obtained by removing the compound of Formula IV-a using methyl acetate and hexane or methanol and water, and this removal process is performed through a purification process of the compound of Formula IV-a. Can be performed. The compound of formula IV obtained through this, it was confirmed that the purity of 95% or more when analyzed by HPLC.

The purification process can be carried out in two stages, for example, in the purification process, ethyl acetate and hexane are used in a conventional suitable ratio required for purification, for example, in a volume ratio of 1: 5 to 20, or methanol and water. Can be used in the usual appropriate ratios required for purification, for example 1: 1 by volume.

In one preferred embodiment, the process comprises (i) reacting a compound of formula V with an acetate compound to obtain a compound of formula VI; (ii) reacting the compound of formula VI with pyrrolidine to yield a compound of formula VII; And (iii) reacting the compound of formula VII with acetylchloride to obtain a compound of formula VIII.

Step (i) is a step of reacting the compound of formula V with an acetate compound to obtain a compound of formula VI.

(VI)

(VI)

In one preferred embodiment, the step (i) is a compound of formula VI by reacting a compound of formula Va separated in a mixture of a compound of formula Va and a compound of formula Vb with hydrogen peroxide or m-chloroperbenzoic acid Can be obtained.

(V-a)

(Va)

(V-b)

(Vb)

In one preferred embodiment, the step (i) using the compound of formula V and isopropenyl acetate, 10 to 20 hours in the temperature range of 70 to 120 ℃, preferably 13 to 15 at 90 to 110 ℃ By reacting for a time, a compound of formula Va can be obtained, and the compound of formula Va can be obtained in high yield.

The compound of Formula V-a may react with hydrogen peroxide or m-chloroperbenzoic acid and the like, and the hydrogen peroxide or m-chloroperbenzoic acid may be used in an amount of 1.0 to 1.2 equivalents (atomic weight / atom: eq).

In some cases, during the preparation of the compound of Formula V-a, the compound of Formula V-b may be produced as a dispersion, and the compound of Formula V-b may be generated in an area ratio of about 10% during HPLC analysis.

Thus, the step of separating the compound of the formula Va through the recrystallization method using a mixture of methanol and water may be additionally included, the compound of the formula Va obtained through this, the purity when analyzed by HPLC more than 97% I could confirm that.

In this case, the mixed liquid of methanol and water may be mixed in a volume ratio of 1 to 3: 5 to 20, in consideration of the amount of the mixture of the compound of the formula Va and the compound of the formula Vb. It can be mixed in volume ratio.

Step (ii) is a step of reacting the compound of formula VI with pyrrolidine to obtain a compound of formula VII.

(VII)

(VII)

In some cases, 2β- (4-morpholinyl) -16β- (1-pyrrolidinyl) -5α-androstan-3α-ol-17, which is a compound of formula VI-a, may be obtained during the process of obtaining the compound of formula VII. -One compound can be produced, in which case the compound of formula VI-a can be used in the next reaction without further separation and purification.

(VI-a)

(VI-a)

In step (ii), the compound of Formula VI-a may be reacted with a reducing agent to obtain a compound of Formula VII, and as the reducing agent, sodium borohydride may be used.

Step (iii) is a step of reacting the compound of formula VII with acetylchloride to obtain a compound of formula VIII.

(VIII)

(VIII)

In some cases, a compound of formula VIII-a may be produced as a dispersion at about 5% area ratio in HPLC analysis. In this case, step (iii) may further comprise the step of removing the compound of formula VIII-a.

(VIII-a)

(VIII-a)

In order to remove the compound of Formula VIII-a, when subjected to a separation and purification process, the compound of Formula VIII may be obtained with high purity and high quality of 98% or more in HPLC analysis.

The locuronium bromide compound may be produced by the reaction of the compound of formula (V) and allyl bromide in an aprotic solvent or an inactivating solvent, and in the case of obtaining roqueronium bromide through the preparation method according to the present invention, Rhonium bromide may be obtained with high purity of at least about 99% by HPLC analysis.

The aprotic solvent or inactivating solvent is not particularly limited, but may be tetra hydrofuran, chloroform, dichloromethane, diethyl ether, t-butyl dimethyl ether, ether, methylene chloride or carbon tetrachloride, preferably diethyl ether or t -Butyl dimethyl ether.

The present invention also relates to a 2α, 3α-epoxy-5α-androstan-17-one compound of formula (IV) used for the preparation of a rocuronium bromide compound, wherein the novel structure synthesized by the inventor of the present application Compound.

(IV)

(IV)

Hereinafter, the present invention will be described in more detail with reference to Examples, but the following Examples are provided to illustrate the present invention, and the scope of the present invention is not limited thereto.

Preferred examples of the reaction scheme for preparing the rocuronium bromide compound according to the present invention is shown in Scheme 2 below, the specific method for preparing the compound of each step is as follows, the present invention is shown in Scheme 2 and It is not limited to the embodiments.

Scheme 2

Preparation Example 1 Preparation of Androsterone p-Toluenesulfonate

300 g of epiandrosterone was introduced into a reactor with 1000 mL of pyridine, and then 300 g of p-toluenesulfonyl chloride was added dropwise at room temperature, followed by stirring at 35 ° C for 6 hours. After the reaction was completed, the reaction solution was added to 10 L of water at 0 ° C to 5 ° C, and stirred for 1 hour to precipitate crystals. The resulting solid was filtered and washed with 2 L of cooled water and then vacuum dried at 45 ° C. for 12 hours to give 455 g of the white desired compound.

(98.9% yield). mp: 162 ° C.-164 ° C.

Production Example 2 5α-androst-2-ene-17-one (IX)

100 g of androsterone p-toluenesulfonate was introduced into the reactor, and 300 mL of 2,6-dimethylpyridine was added at room temperature. The reaction solution was warmed up to 140 ° C. and then stirred for 8 hours. After the reaction was completed, the reaction mixture was cooled and added to 5 L of water at 0-5 ° C. The precipitated crystals were stirred for 1 hour, filtered, washed with 3 L of cooled water, and then vacuum dried at 45 ° C. for 10 hours to obtain 38 g of a white target compound.

(63% yield), mp: 106 ° C.-108 ° C.

Example 1 Preparation of 2α, 3α-Epoxy-5α-Androstan-17-one (IV)

170 g of 5α-androst-2-ene-17-one was added to the reactor with 1.8 L of diethyl ether to dissolve it, and thereafter, 111 g (1.05 eq) of m-chloroperbenzoic acid was dissolved in 300 mL of diethyl ether and dissolved at 5 ° C. Below 3 hours was added dropwise. After 18 hours of stirring at 20 ° C., the resulting crystals were filtered to yield 117 g (65%) of crude crystals. 50 mL of methanol was added to dissolve the crude crystals, and then 5 L of the dissolved solution was added dropwise with cooling water, followed by stirring for 1 hour to obtain crystals. The obtained crystals were filtered, washed with 200 mL of cooling water, and then vacuum dried at 45 ° C. for 10 hours to obtain 99 g (55%) of the white desired compound.

mp 132-134 ° C .; [α] ²⁰ + D = + 27 ° C.

¹ HNMRδ: 1.16 (s, 3H), 1.26 (s, 3H), 1.27-1.52 (m, 6H), 1.37-1.62 (m, 2H), 1.49-1.65 (m, 2H), 1.40 (m, 1H) , 1.41 (m, 2H), 1.51-1.76 (m, 2H), 1.63 (m, 1H), 2.87 (m, 2H)

Example 2 Preparation of 2β- (4-morpholinyl) -androstan-3α-ol-17-one (V)

99 g (0.34 mol) of 2,3-epoxy-5-androstan-17-one, 31.4 g (1.05 eq) of morpholine and 35 mL of water were added to the reactor, and p-toluenesulfate was added at 20-24 ° C. Nickel acid 68g (1.15eq) was added and refluxed for 35 to 40 hours, then cooled to 20-24 ° C and added to 100 mL of 4% 2% sodium carbonate solution. After stirring for 1 hour, the precipitated crystals were filtered, washed with 100 mL of cooling water, and then vacuum dried at 40 ° C. for 20 hours to obtain 110 g (85%) of the white target compound.

mp: 168 ° C., [α] _D ²⁰ +35.0 (c = 1.0 in CHCl ₃ ).

¹ HNMRδ: 1.16 (s, 3H), 1.26 (s, 3H), 1.40 (m, 1H), 1.41 (m, 2H), 1.52 (m, 6H), 1.54 (m, 2H), 1.64 (m, 1H ), 1.68 (m, 2H), 1.77 (m, 2H), 2.10 (m, 4H), 2.37 (t, 4H), 2.67 (m, 1H), 3.42 (m, 1H), 3.69 (t, 4H) , 4.88 (brs, 1 H)

Example 3 Preparation of 2β- (4-morpholinyl) -3α-ol-16α, 17α-epoxy-17β-acetoxy-5α-androstane (VI)

1. Preparation of 2β- (4-morpholinyl) -3α-ol-17β-acetoxy-5α-androstan-2-ene (V-a)

110 g (0.293 mol) of 2β- (4-morpholinyl) -androstan-3α-ol-17-one and 32.3 g (1.1 eq) of isopropenyl acetate were added to a reactor, and cooled to 0 ° C., followed by 2 mL of sulfuric acid. It was added under nitrogen conditions and then warmed to reflux at 100 ° C. for 14 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, and then charged into 800 mL of 5% sodium hydrogen carbonate solution and 1 L of n-pentane solution. The organic layer was separated and concentrated, and 50 mL of methanol was added to the obtained oil to dissolve it, and then crystallized by adding 500 mL of cooling water. The obtained crystals were filtered, washed with 50 mL of cooling water, and dried in vacuo at 40 ° C. for 10 hours to give 104 g (85%) of the white desired compound.

2. Preparation of 2β- (4-morpholinyl) -3α-ol-16α, 17α-epoxy-17β-acetoxy-5α-androstane (VI)

104 g (0.248 mol) of 2β- (4-morpholinyl) -3α-ol-17β-acetoxy-5α-androstan-2-ene and 1.2 L of diethyl ether were added to a reactor, and m-chloroperbenzoic acid was added. 47 g (1.1 eq) was dissolved in 100 mL of diethyl ether and added dropwise at 5 ° C. or lower for 3 hours. After dropping, the mixture was stirred at 20 ° C. for 15 hours to crystallize, and then filtered and recrystallized using diethyl ether to obtain 86 g (80%) of a white crystalline compound.

mp 174-177 ° C; [α] ²⁰ + D + 48 ° C.

¹ HNMRδ: 1.18 (s, 6H), 1.42 (m, 2H), 1.44 (m, 2H), 1.51 (m, 2H), 1.52 (m, 6H), 1.55 (m, 2H), 1.69 (m, 2H ), 2.02 (s, 3H), 2.37 (t, 4H), 2.66 (m, 1H), 3.42 (m, 1H), 3.69 (t, 4H), 4.92 (brs, 1H)

Example 4 Preparation of 2β- (4-morpholinyl) -16β- (1-pyrrolidinyl) -5α-androstan-3α, 17β-diol (VII)

1. Preparation of 2β- (4-morpholinyl) -3α-ol-16β- (1-pyrrolidinyl) -5α-androstan-17-one (VI-a)

86 g (0.198 mol) of 2β- (4-morpholinyl) -3α-ol-16α, 17α-epoxy-17β-acetoxy-5α-androstane was dissolved in 800 mL, and 60 mL of 4N sodium hydroxide solution was added at room temperature. . After refluxing the reaction solution for 30 minutes, 14.7 g (1.05eq) of pyrrolidine was added at 40 ° C, and the reaction was refluxed for about 1 hour. After the reaction was completed, the reaction mixture was cooled to room temperature, crystallized by adding 800 mL of cooling water, stirred for 1 hour, and filtered. Methanol 200mL was added to the obtained crude crystals, it was refluxed for 30 minutes, 500mL of water was added slowly, and it stirred at 65-70 degreeC for 30 minutes. After cooling the reaction solution to 0-5 ℃, the resulting crystals were filtered, washed with 100 mL of water and then vacuum dried at 40 ℃ for 10 hours to give 77.4 g (88%) of the white target compound.

mp: 185 ° C., [α] _D ²⁰ +79 (c = 1.0 in CHCl ₃ ).

2. Preparation of 2β- (4-morpholinyl) -16β- (1-pyrrolidinyl) -5α-androstan-3α, 17β-diol (VII)

77.4 g (0.174 mol) of 2β- (4-morpholinyl) -3α-ol-16β- (1-pyrrolidinyl) -5α-androstan-17-one and 1000 mL of methanol were added to the reactor, and then -10 Cooled to C. Sodium borohydride 12g (1.8eq) was slowly added to the reaction solution, and reacted at 20-24 ° C for 3 hours. 1000 mL of methylene chloride and 1000 mL of water were added to the reaction solution, and the layers were separated and the organic layer was concentrated to obtain crude crystals. Methanol 200mL was added to the crude crystals, heated and dissolved, and 1000mL of water was added at 20 ° C to obtain crystals, filtered, and washed with 100mL of water. Vacuum drying at 40 ° C. for 10 hours yielded 67.6 g (87%) of the white desired compound.

mp: 225 ° C., [α] _D ²⁰ +82.0 (c = 1.0 in CHCl ₃ ).

¹ HNMRδ: 1.18 (s, 6H), 1.40 (m, 2H), 1.42 (m, 2H), 1.48 (m, 2H), 1.53 (m, 6H), 1.55 (m, 2H), 1.58 (m, 4H ), 1.69 (m, 4H), 2.22 (m, 4H), 2.36 (t, 4H), 2.66 (m, 1H), 3.42 (m, 1H), 3.69 (t, 4H), 4.92 (brs, 1H)

Example 5 Preparation of 2β- (4-morpholinyl) -16β- (1-pyrrolidinyl) -5α-androstan-3α, 17β-diol-17 acetate (VIII)

67.6 g (0.151 mol) of 2β- (4-morpholinyl) -16β- (1-pyrrolidinyl) -5α-androstan-3α, 17β-diol, 1000 mL of methylene chloride and 17.7 g (1.5eq) of acetyl chloride The mixture was added to the reactor and stirred at 35 ° C. for 4 hours, 200 mL of 10% aqueous hydrochloric acid solution was added thereto, followed by layer separation to separate the water layer, followed by stirring at 50 ° C. for 1 hour. 180 g of potasum hydrocarbonate, 700 ml of water, and 300 ml of methylene chloride were added to the reaction solution while maintaining the temperature below 10 ° C. The organic layer was separated, concentrated to precipitate crystals, and then dried in vacuo at 40 ° C. for 10 hours to give 65 g (88%) of the white desired compound.

¹ HNMRδ: 1.17 (s, 6H), 1.40 (m, 2H), 1.42 (m, 2H), 1.48 (m, 2H), 1.53 (m, 6H), 1.55 (m, 2H), 1.59 (m, 4H ), 1.66 (m, 4H), 2.01 (s, 3H), 2.22 (m, 2H), 2.36 (t, 4H), 2.66 (m, 1H), 3.24 (m, 1H), 3.42 (m, 1H) , 3.69 (t, 4H), 4.21 (m, 1H), 4.92 (brs, 1H)

Example 6 1-[(2β, 3α, 5α, 16β, 17β) -17- (acetyloxy) -3-hydroxy-2- (4-morpholinyl) androstan-16-yl] -1 Preparation of-(2-propenyl) pyrrolidium bromide

65 g (0.133 mol) of 2β- (4-morpholinyl) -16β- (1-pyrrolidinyl) -5α-androstan-3α, 17β-diol-17 acetate and 980 mL of methylene chloride were added to the reactor and 20-22 After dissolving at ℃, the mixture was concentrated under reduced pressure to remove 480 mL. 22.8 mL of allyl bromide was dissolved in 160 mL of methylene chloride, 34 g of sodium carbonate was added thereto, stirred for 30 minutes, and then the filtrate was filtered through 2β- (4-morpholinyl) -16β- (1-pyrrolidinyl) -5α-. Androstan-3α, 17β-diol-17 acetate solution. The reaction solution was stirred at 40 ° C. for about 20 hours, then cooled to room temperature and concentrated under reduced pressure at 20 ° C. or lower. 600 mL of methylene chloride was added to the filtrate, and the filtrate was slowly added dropwise to 4.5 L of diethyl ether to form crystals. After stirring for 1 hour, the mixture was filtered and dried in vacuo at 40 ° C for 10 hours to give 72 g (89%) of the white desired compound.

mp: 209 ° C., [α] _D ²⁰ +29.8 (c = 1.0 in CHCl ₃ ).

¹ HNMRδ: 1.19 (s, 6H), 1.40 (m, 2H), 1.43 (m, 2H), 1.48 (m, 2H), 1.52 (m, 6H), 1.55 (m, 2H), 1.66 (m, 2H ), 1.72 (m, 4H), 2.00 (m, 2H), 2.03 (s, 3H), 2.36 (t, 4H), 2.66 (m, 1H), 3.24 (m, 4H), 3.42 (m, 1H) , 3.69 (t, 4H), 3.91 (d, 2H), 4.21 (m, 1H), 4.56 (m, 1H), 4.92 (brs, 1H), 4.98 (dd, 1H), 5.06 (dd, 1H), 5.72 (dd, 1 H)

Those skilled in the art to which the present invention pertains will be able to perform various applications and modifications within the scope of the present invention based on the above contents.

Claims (13)

A method for preparing a Rocuronium Bromide compound comprising reacting a compound of Formula IV with morpholine.

(IV) The method of claim 1, The manufacturing method, (i) reacting a compound of formula V with an acetate compound to obtain a compound of formula VI; (ii) reacting the compound of formula VI with pyrrolidine to yield a compound of formula VII; And (iii) reacting the compound of formula (VII) with acetylchloride to obtain a compound of formula (VIII); the method of preparing rocuronium bromide compound further comprising:

(V)

(VI)

(VII)

(VIII) The method of claim 1, In the preparation method, a compound of formula (IV) is reacted with hydrogen peroxide or m-chloroperbenzoic acid in the presence of a solvent before the reaction of the compound of formula (IV) with morpholine to obtain a compound of formula (IV). Method for producing a rocronium bromide compound, characterized in that it further comprises the step of.

(IX) The method of claim 3, wherein Said solvent is tetrahydrofuran, chloroform, dichloromethane, diethyl ether, t-butyl dimethyl ether, ether, methylene chloride and carbon tetrachloride, the method for producing a rocuronium bromide compound, characterized in that at least one selected from the group consisting of. The method of claim 3, wherein The hydrogen peroxide or m-chloroperbenzoic acid is a method for producing a rocuronium bromide compound, characterized in that used in 1.0 to 1.2 equivalents (atomic weight / valence: eq). The method of claim 3, wherein The reaction is a method for producing a rocuronium bromide compound, characterized in that for 2 to 4 hours at a temperature of -5 to 10 ℃. The method of claim 1, The preparation method further comprises the step of removing the compound of formula (IV-a) using methyl acetate and hexane, or methanol and water.

(IV-a) The method of claim 2, In step (i), the compound of formula Va is reacted with an acetate compound, and then the compound of formula Va is separated from a mixture of a compound of formula Va and a compound of formula Vb, and the compound of formula Va and hydrogen peroxide or m- A process for preparing rocuronium bromide compound, wherein the chloroperbenzoic acid is reacted to obtain a compound of formula VI.

(Va)

(Vb) The method of claim 2, The step (i) is a method for producing a rocuronium bromide compound, characterized in that to react the compound of formula V and isopropenyl acetate at a temperature of 70 to 120 ℃ 10 to 20 hours to obtain a compound of formula (V-a).

(Va) The method of claim 8, The step (i) is a method for producing a rocuronium bromide compound, characterized in that to remove the compound of formula V-b using methanol and water mixed in a volume ratio of 1 to 3: 5 to 20.

(Vb) The method of claim 2, Step (ii) is a method of preparing a rocuronium bromide compound, characterized in that by reacting a compound of formula (VI) with pyrrolidine and then reacting a compound of formula (VI-a) with a reducing agent .

(VI-a) The method of claim 2, The step (iii) is a method for producing a rocuronium bromide compound, characterized in that by reacting a compound of formula (VII) with acetyl chloride to remove the compound of formula (VIII-a) to obtain a compound of formula (VIII).

(VIII-a) delete