KR20030085658A - An improved synthetic method of bambuterol - Google Patents

Abstract

PURPOSE: A method for preparing bambuterol is provided, to improve the yield, to reduce the manufacturing cost and to allow the mass production to be possible by reducing the reaction temperature and pressure. CONSTITUTION: The method comprises the steps of preparing bis-3,5-(N,N-dimethylcarbamoyloxy)-acetophenone from 3',5'-dihydroxyacetophenone by acylation; brominating the bis-3,5-(N,N-dimethylcarbamoyloxy)-acetophenone with 1.2 equivalent of bromine to prepare bis-3',5'-(N,N-dimethylcarbamoyloxy)-2-bromo-acetophenone; alkylating the bis-3',5'-(N,N-dimethylcarbamoyloxy)-2-bromo-acetophenone with 3 equivalent of N-benzyl-tert-butylamine to prepare bis-3',5'-(N,N-dimethylcarbamoyloxy)-2-(N-benzyl-tert-butyl)amino-acetophenone; and reducing the bis-3',5'-(N,N-dimethylcarbamoyloxy)-2-(N-benzyl-tert-butyl)amino-acetophenone by treating it with 2.5 equivalent of NaBH4 and hydrogenating the obtained one in the presence of 1.3 equivalent of benzyl chloride and 10% Pd/C at atmospheric pressure to prepare bambuterol.

Description

Improved Synthesis of Bambuterol {AN IMPROVED SYNTHETIC METHOD OF BAMBUTEROL}

The present invention relates to an improved process for the synthesis of bambuterol, and more particularly to bambuterol (1- [bis- (3 ', 5'-N, N-dimethyl) from 3', 5'-dihydroxyacetophenone. Carbamoyloxy) phenyl] -2-N-tert-butylaminoethanol hydrochloride) in the process of synthesizing the equivalent amount and reaction conditions of the reactants of each step by the milder and easier reactions yields greatly improved yield To obtain terrols.

Bambuterol is a bronchodilator that is an α2-adrenergic agonist and is an effective drug for chronic bronchitis, emphysema, and other lung-related diseases involving bronchial asthma, bronchospasm. Bambuterol is a prodrug of terbutaline, which is absorbed in vivo and then slowly metabolized to be converted to the active metabolite, terbutaline, resulting in pharmacological action. Bambuterol is represented by the following Chemical Formula 1.

Conventionally, the synthesis of bambuterol is a first step of preparing bis-3,5- (N, N-dimethylcarbamoyloxy) -acetophenone through an acylation process from 3 ', 5'-dihydroxyacetophenone; A second step of preparing bis-3 ', 5'-(N, N-dimethylcarbamoyloxy) -2-bromo-acetophenone from the bromide process therefrom; A third step of preparing bis-3 ', 5'-(N, N-dimethylcarbamoyloxy) -2- (N-benzyl tert-butyl) amino-acetophenone through an alkylation process therefrom; A fourth process for preparing 1- [bis- (3 ', 5'-N, N-dimethylcarbamoyloxy) phenyl] -2-N-tert-butylaminoethanol hydrochloride, ie, bambuterol, from the reduction process It consists of; (Korean Patent Publication No. 83-6174, US 4419364)

Looking at each step,

In the first step, 3 equivalents of N, N-dimethylcarbamoyl chloride was added to a solution of 3 ', 5'-dihydroxyacetophenone and anhydrous pyridine, followed by reaction at a temperature of 60 to 70 ° C. for 18 hours. , 5- (N, N-dimethylcarbamoyloxy) -acetophenone is prepared.

In the second step, 1 equivalent of bromine and dioxane were added dropwise to the solution of bis-3,5- (N, N-dimethylcarbamoyloxy) -acetophenone and dioxane prepared in the first step at 35 ° C. The reaction was carried out for a period of time to prepare bis-3 ', 5'-(N, N-dimethylcarbamoyloxy) -2-bromo-acetophenone.

In the third step, N-benzyl tert-butylamine was added to a solution of bis-3 ', 5'-(N, N-dimethylcarbamoyloxy) -2-bromo-acetophenone and acetone prepared in the second step. A solution of 2 equivalents and acetone was added and refluxed for 18 hours to give bis-3 ', 5'-(N, N-dimethylcarbamoyloxy) -2- (N-benzyl tert-butyl) amino-acetophenone. Manufacture.

In the fourth step benzyl solution of bis-3 ', 5'-(N, N-dimethylcarbamoyloxy) -2- (N-benzyl tert-butyl) amino-acetophenone and ethanol obtained in the third step Hydrogenated in the presence of chloride and 10% Pd / C, the final desired bambuterol, i.e., 1- [bis- (3 ', 5'-N, N-dimethylcarbamoyloxy) phenyl] -2-N-tertbutylamino Obtain ethanol hydrochloride. At this time, the hydrogenation reaction conditions are reacted for 24 hours at 50 psi pressure and 50 ℃ high temperature, high pressure.

As described above, the conventional bambuterol synthesis method consists of a catalytic reaction in which reaction conditions are difficult and a high temperature and high pressure process in which facility management is difficult, and therefore requires a lot of skill and experience in selecting and developing optimum conditions for the reaction. Difficult, the average yield of each known step was about 60-70% and the overall yield of the final target bambuterol from the starting material was about 20%.

Although it is possible to synthesize bambuterol by the conventional method, it is possible to lower the production cost and to improve the yield in order to produce a large quantity, and the reaction condition is a mild reaction of low temperature and low pressure, which is easy to work instead of the high temperature and high pressure reaction. There is a need to improve.

Accordingly, an object of the present invention is to provide a method for synthesizing bambuterol, the yield of which is greatly improved by controlling the use equivalents and reaction conditions of the reactants.

In addition, in the present invention, in order to provide a method for synthesizing bambuterol, which is easier to manufacture, the process of high temperature (50 ° C.) and high pressure (50 psi ) reactions in which reaction conditions are difficult and mass production is difficult is performed at room temperature and atmospheric pressure. It is an object of the present invention to provide a method for synthesizing bambuterol, which is easy to manage each reaction process in the synthesis process and can significantly lower the production cost compared to the conventional method by improving and simplifying the process.

Other objects and advantages of the present invention will be described below and will be better understood by examples of the present invention.

In the present invention to achieve the above object,

Preparing a bis-3,5- (N, N-dimethylcarbamoyloxy) -acetophenone from an 3 ', 5'-dihydroxyacetophenone via an acylation process; Preparing a bis-3 ', 5'-(N, N-dimethylcarbamoyloxy) -2-bromo-acetophenone therefrom; Preparing a bis-3 ', 5'-(N, N-dimethylcarbamoyloxy) -2- (N-benzyl tert-butyl) amino-acetophenone from the alkylation process therefrom; In the method of synthesizing bambuterol from the step of obtaining bambuterol from the reduction process,

In the bromination process, 1.2 equivalents of bromine is reacted with bis-3,5- (N, N-dimethylcarbamoyloxy) -acetophenone,

In the alkylation process, 3 equivalents of N-benzyl tert-butylamine is reacted with bis-3 ', 5'-(N, N-dimethylcarbamoyloxy) -2-bromo-acetophenone,

The reduction process is performed by treating bis-3 ', 5'-(N, N-dimethylcarbamoyloxy) -2- (N-benzyl tert-butyl) amino-acetophenone with 2.5 equivalents of NaBH ₄ , followed by benzyl There is provided an improved process for the synthesis of bambuterol in which the yield of milder conditions is greatly improved, characterized by hydrogenation at room temperature, atmospheric pressure in the presence of 1.3 equivalents of chloride and 10% Pd / C.

Hereinafter, the synthesis process of bambuterol according to the present invention will be described for each step.

Preparation step of bis-3,5- (N, N-dimethylcarbamoyloxy) -acetophenone

3 equivalents of N, N-dimethylcarbamoyl chloride was added to a solution of 3 ', 5'-dihydroxyacetophenone and anhydrous pyridine, and then reacted at a temperature of 70 ° C. for 18 hours. The residue is treated with ethyl acetate and water. The treated ethyl acetate layer was dried over MgSO ₄ and evaporated. The residue was dissolved in isopropyl alcohol, and petroleum ether was added dropwise to recrystallize to give the desired compound bis-3,5- (N, N-dimethylcarbamoyloxy. Obtain acetophenone. The yield of this stage is usually 75% or more.

Preparation step of bis-3 ', 5'-(N, N-dimethylcarbamoyloxy) -2-bromo-acetophenone

Bis-3,5- (N, N-dimethylcarbamoyloxy) -acetophenone obtained in the previous step was added to dioxane and stirred, and a solution of 1.2 equivalents of bromine diluted in dioxane was added dropwise for 1 hour 30 minutes. . After the addition, the mixture was allowed to react for 1 hour, and when the reaction was completed, the mixture was evaporated, and then the solid residue was dissolved in isopropyl alcohol, and recrystallized by dropwise addition of petroleum ether to bis-3 ', 5'-(N, N-dimethylcarbamoyloxy ) -2-bromo-acetophenone is obtained. The yield of this step in the present invention is usually 95% or more.

Preparation step of bis-3 ', 5'-(N, N-dimethylcarbamoyloxy) -2- (N-benzyl tert-butyl) amino-acetophenone

Bis-3 ', 5'-(N, N-dimethylcarbamoyloxy) -2-bromo-acetophenone prepared in the previous step was added to acetone and stirred, followed by 3 equivalents of N-benzyl tert-butylamine The solution diluted in acetone was added dropwise for 1 hour. After completion of the dropwise addition, the mixture was heated to reflux for 18 hours, and when the reaction was completed, the solid in the mixture was filtered, evaporated, and the residue was dissolved in isopropyl alcohol, and recrystallized by dropwise addition of petroleum ether, to give bis-3 ', 5'-( N, N-dimethylcarbamoyloxy) -2- (N-benzyl tert-butyl) amino-acetophenone is obtained. The yield of this step in the present invention is usually at least 80%.

Preparation Step of 1- [bis- (3 ', 5'-N, N-dimethylcarbamoyloxy) phenyl] -2-N-tert-butylaminoethanol hydrochloride

Bis-3 ', 5'-(N, N-dimethylcarbamoyloxy) -2- (N-benzyl tert-butyl) amino-acetophenone prepared in the previous step was added to methanol and stirred, followed by NaBH ₄ 2.5 Treatment with equivalents then hydrogenation of the remaining reactants in the presence of 1.3 equivalents of benzylchloride and 10% Pd / C. The hydrogenation reaction is allowed to react for 6 hours at atmospheric pressure and room temperature. After the reaction was completed, the catalyst in the mixture was filtered, evaporated, the residue was dissolved in isopropyl alcohol, filtered, and then recrystallized by dropwise addition of diethyl ether to the filtrate to obtain 1- [bis- (3 ', 5'-N, N-dimethylcarbamoyloxy) phenyl] -2-N-tert-butylaminoethanol hydrochloride, ie bambuterol. The yield of this step in the present invention is usually at least 65%.

In the present invention, in order to improve the yield, the use equivalent of bromine in the bromination process and the use equivalent of N-benzyl tert-butylamine in the alkylation process are respectively adjusted to 1.2 equivalents and 3 equivalents, and the manufacturing process is easily facilitated. Thus, the final reduction process is improved to mild conditions of room temperature and atmospheric pressure while maintaining similar yields under conventional high temperature and high pressure conditions to enable mass production. Thus, the bambuterol synthesis method of the present invention in which the use equivalents and reaction conditions of the reactants are controlled shows a greatly improved yield of about 2 times compared to the existing method in the overall yield.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, the examples are only for illustrating the present invention and the scope of the present invention is not limited by the following examples.

Example

1) Preparation of Bis-3,5- (N, N-dimethylcarbamoyloxy) -acetophenone

63.7 ml (3eq) of N, N-dimethylcarbamoyl chloride was added to a solution of 35.0 g (230 mmol) of 3 ', 5'-dihydroxyacetophenone and 160 ml of anhydrous pyridine, and then reacted at a temperature of 70 ° C. for 18 hours. . After confirming that the reaction was completed by TLC (EA: n-Hexanes = 1: 1), the mixture was evaporated, and the residue was treated with ethyl acetate and water. The treated ethyl acetate layer was dried over MgSO ₄ and evaporated. After evaporation, the residue was dissolved in 140 mL of isopropyl alcohol and recrystallized by dropwise addition of 910 mL of petroleum ether. NMR confirmed that the obtained compound was the desired bis-3,5- (N, N-dimethylcarbamoyloxy) -acetophenone.

Yield: 53.3 g Yield: 78.8% m.p 77.0-78.0 ° C

¹ H NMR (300 MHz, CDCl ₃ ), δ 2.59 (3H, s), 3.07 (12H, s), 7.40 (3H, m)

2) Preparation of Bis-3 ', 5'-(N, N-dimethylcarbamoyloxy) -2-bromo-acetophenone

51.0 g (173 mmol) of bis-3,5- (N, N-dimethylcarbamoyloxy) -acetophenone obtained in the above step and 175 ml of dioxane were added thereto, followed by stirring. Then, 10.2 ml (1.2 eq) of bromine was added to dioxane 200. The solution diluted in mL was added dropwise for 1 hour 30 minutes. After 1 hour of addition, the reaction was completed by TLC (EA: n-Hexanes = 1: 1), the mixture was evaporated and the solid residue was dissolved in 220 ml of isopropyl alcohol and 450 ml of petroleum ether was added. Recrystallization was added dropwise. NMR confirmed the synthesis of the desired compound bis-3 ', 5'-(N, N-dimethylcarbamoyloxy) -2-bromo-acetophenone.

Yield: 61.8 g Yield: 95.5% m.p 120.4-121.4 ° C

¹ H NMR (300MHz, CDCl ₃ ), δ3.07 (12H, s), 4.43 (2H, s), 7.44 (3H, m)

3) Preparation of bis-3 ', 5'-(N, N-dimethylcarbamoyloxy) -2- (N-benzyl tert-butyl) amino-acetophenone

Bis-3 ', 5'-(N, N-dimethylcarbamoyloxy) -2-bromo-acetophenone 60.0 g (161 mmol) obtained in the above step and 600 ml of acetone were added thereto, followed by stirring, followed by N-benzyl-3. A solution of 73.0 mL (3 eq) of tert-butylamine diluted in 800 mL of acetone was added dropwise for 1 hour. After the dropwise addition was heated to reflux for 18 hours. TLC (EA: n-Hexanes = 1: 1) confirmed that the reaction was completed, the solid in the mixture was filtered, evaporated, the residue was dissolved in 280 ml isopropyl alcohol, and 280 ml of petroleum ether was added dropwise to recrystallize. It was. NMR confirmed the synthesis of the desired compound bis-3 ', 5'-(N, N-dimethylcarbamoyloxy) -2- (N-benzyl tert-butyl) amino-acetophenone.

Yield: 59.78 g Yield: 81.6% m.p: 71.0-72.5 ° C

¹ H NMR (300MHz, CDCl ₃ ), δ1.22 (9H, s), 3.06 (12H, s), 3.87 (2H, s), 3.93 (2H, s), 7.28 (8H, m)

4) Preparation of 1- [bis- (3 ', 5'-N, N-dimethylcarbamoyloxy) phenyl] -2-N-tert-butylaminoethanol hydrochloride

15 g (32.9 mmol) of bis-3 ', 5'-(N, N-dimethylcarbamoyloxy) -2- (N-benzyl tert-butyl) amino-acetophenone obtained in the above step and 200 ml of methanol were added thereto. After stirring, 3.1 g (2.5 eq) of NaBH ₄ was treated and the residual reaction was hydrogenated with 4.93 mL (1.3 eq) of benzyl chloride and 700 mg of 10% Pd / C. At this time, the hydrogenation reaction conditions were allowed to react for 6 hours at atmospheric pressure, room temperature. After completion of the reaction by TLC (EA: n-Hexane = 2: 1), the catalyst in the mixture was filtered, evaporated, and the residue was dissolved in 90 mL of isopropyl alcohol and filtered. 90 ml of ethyl ether was added dropwise to recrystallize. NMR confirmed the synthesis of the desired compound 1- [bis- (3 ', 5'-N, N-dimethylcarbamoyloxy) phenyl] -2-N-tert-butylaminoethanol hydrochloride, ie bambuterol. .

Yield: 8.80 g Yield: 66.0% m.p: 225.0-226.5 ° C

¹ H NMR (300MHz, D ₂ O), δ1.43 (9H, s), 3.03 (12H, d), 3.17 (2H, m), 4.70 (DOH), 5.10 (1H, q), 7.09 (3H, m)

Comparative example

The bambuterol was synthesized according to a known synthesis process of bambuterol.

One)

280 ml (3 equivalents) of N, N-dimethylcarbamoyl chloride was added to a solution of 152 g of 3 ', 5'-dihydroxyacetophenone and 700 ml of anhydrous pyridine, followed by stirring for 18 hours at a temperature of 60 to 70 ° C. I was. The mixture was evaporated in vacuo and the residue was treated with a mixture of diethyl ether and water. The formed aqueous layer was extracted with diethyl ether, the diethyl ether layers were combined, washed with water, and dried over MgSO ₄ . After evaporation, the residue was recrystallized from isopropyl alcohol and petroleum ether to prepare bis-3,5- (N, N-dimethylcarbamoyloxy) -acetophenone, which was confirmed by NMR.

Yield: 61.3% m.p 77.0-78.0 ° C

¹ H NMR (300 MHz, CDCl ₃ ), δ 2.59 (3H, s), 3.07 (12H, s), 7.40 (3H, m)

2)

To a solution of 180 g of bis-3,5- (N, N-dimethylcarbamoyloxy) -acetophenone obtained above and 700 ml of dioxane, a solution of 31 ml (1 equivalent) of bromine and 200 ml of dioxane was added dropwise, 35 Stir at 1 ° C. for 1 h. The residue formed after vacuum and evaporation was recrystallized from isopropyl alcohol and petroleum ether to obtain bis-3 ', 5'-(N, N-dimethylcarbamoyloxy) -2-bromo-acetophenone, which was confirmed by NMR. It was.

Yield: 74.0% m.p 120.4-121.4 ° C.

¹ H NMR (300MHz, CDCl ₃ ), δ3.07 (12H, s), 4.43 (2H, s), 7.44 (3H, m)

3)

4.9 g of N-benzyl tert-butylamine in a solution of 5.6 g of bis-3 ', 5'-(N, N-dimethylcarbamoyloxy) -2-bromo-acetophenone and 75 ml of acetone obtained above (2 equivalents) and a solution of 30 ml of acetone were added and refluxed for 18 hours. After the reaction was completed, the mixture was filtered and evaporated in vacuo, and the residue was dissolved in diethyl ether, and petroleum ether was added, and then a yellow precipitate formed was filtered. Washed with water and then recrystallized from a mixture of isopropyl alcohol and petroleum ether to give bis-3 ', 5'-(N, N-dimethylcarbamoyloxy) -2- (N-benzyl tert-butyl) amino- as a white crystal. Acetophenone was obtained and confirmed by NMR.

Yield: 67.3% m.p: 71.0-72.5 ° C

¹ H NMR (300MHz, CDCl ₃ ), δ1.22 (9H, s), 3.06 (12H, s), 3.87 (2H, s), 3.93 (2H, s), 7.28 (8H, m)

4)

A solution of 78 g of bis-3 ', 5'-(N, N-dimethylcarbamoyloxy) -2- (N-benzyl tert-butyl) amino-acetophenone and 300 ml of ethanol obtained above was 25 ml of benzyl chloride. And hydrogenated in the presence of 3.5 g of 10% Pd / C. At this time, the hydrogenation reaction conditions were reacted for 24 hours at a pressure of 50 psi and a high temperature, high pressure of 50 ℃. After filtering the catalyst, the filtrate was evaporated and dried, and the residue was dissolved and filtered in isopropanol, and then diethyl ether was added to the filtrate to obtain 1- [bis- (3 ', 5'-N, N) as a target compound. -Dimethylcarbamoyloxy) phenyl] -2-N-tert-butylaminoethanol hydrochloride, ie bambuterol, was precipitated. The identity of the product was confirmed by NMR.

Yield: 67.0% m.p: 225.0-226.5 deg.

¹ H NMR (300MHz, D ₂ O), δ1.43 (9H, s), 3.03 (12H, d), 3.17 (2H, m), 4.70 (DOH), 5.10 (1H, q), 7.09 (3H, m)

The result of comparing the said Example and the comparative example is as Table 1 below.

Characteristics by process (reaction conditions and equivalents) yield(%) Example Acylation process work-up solvent Ethyl acetate 78.8% Bromination process Bromine Usage 1.2 equivalents 95.9% Alkylation process N-benzyl tert-butylamine 3 equivalency 81.6% Reduction process Reaction condition Atmospheric pressure, room temperature, 6 hours 66.0% Overall process 40.5% Comparative example Acylation process work-up solvent ether 61.3% Bromination process Bromine Usage 1 equivalent 74.0% Alkylation process N-benzyl tert-butylamine 2 equivalent 67.3% Reduction process Reaction condition 50 psi, 50 ° C, 24 hours 67.0% Whole process 20.4%

As can be seen from the above examples and comparative examples, the synthesis method of bambuterol according to the present invention, unlike the conventional synthesis method, without the need for a high temperature, high pressure device at room temperature, atmospheric pressure more gentle and easy reaction conditions mass Production can be achieved, and in particular, the yield can be greatly improved by optimizing the use amount of the reactants in each step and the reaction conditions, thereby greatly reducing the production cost.

Claims (1)

Preparing a bis-3,5- (N, N-dimethylcarbamoyloxy) -acetophenone from an 3 ', 5'-dihydroxyacetophenone via an acylation process; Preparing a bis-3 ', 5'-(N, N-dimethylcarbamoyloxy) -2-bromo-acetophenone therefrom; Preparing a bis-3 ', 5'-(N, N-dimethylcarbamoyloxy) -2- (N-benzyl tert-butyl) amino-acetophenone from the alkylation process therefrom; In the method of synthesizing bambuterol from the step of obtaining bambuterol from the reduction process, In the bromination process, 1.2 equivalents of bromine is reacted with bis-3,5- (N, N-dimethylcarbamoyloxy) -acetophenone, In the alkylation process, 3 equivalents of N-benzyl tert-butylamine is reacted with bis-3 ', 5'-(N, N-dimethylcarbamoyloxy) -2-bromo-acetophenone, The reduction process is performed by treating bis-3 ', 5'-(N, N-dimethylcarbamoyloxy) -2- (N-benzyl tert-butyl) amino-acetophenone with 2.5 equivalents of NaBH ₄ , followed by benzyl An improved process for the synthesis of bambuterol, characterized by hydrogenation at room temperature and atmospheric pressure in the presence of 1.3 equivalents of chloride and 10% Pd / C.