KR20040045579A - Preparation method of r-form aromatic sulfon amide derivatives - Google Patents

Abstract

PURPOSE: A method for preparing an R-aromatic sulfone amide derivative is provided, to obtain highly pure R-aromatic sulfone amide derivatives economically and stably by using an optical separation method. CONSTITUTION: The method comprises the steps of dissolving a racemic aromatic amide derivative represented by the formula 1 in a mixture solution of phosphate buffer and an organic solvent; and adding penicillin acrylase to the solution and stirring it to prepare an R-aromatic sulfone amide derivative represented by the formula 2. Preferably the organic solvent is selected from the group consisting of ethyl acetate, diethyl ether and isopropyl ether; and the amount of the penicillin acrylase is 0.05-1.0 equivalences based on the weight of the racemic aromatic amide derivative.

Description

Method for producing R-type aromatic sulfonamide derivatives {PREPARATION METHOD OF R-FORM AROMATIC SULFON AMIDE DERIVATIVES}

[Industrial use]

The present invention relates to a method for preparing an R-type aromatic sulfonamide derivative, and more particularly, to an R-type aromatic sulfonamide derivative capable of economically and safely producing a high-purity R-type aromatic sulfonamide derivative using an optical splitting method. It is about a method.

[Prior art]

The optically active R-type aromatic sulfonamide derivative of Formula 2 is a substance useful as a therapeutic agent for prostatic hyperplasia and as an intermediate for preparing an optically active pharmaceutical agent.

[Formula 2]

The R-type aromatic sulfonamide derivative of Chemical Formula 2 is a stereoscopically pure substance in which the three-dimensional composition of the methyl group at the 1-position of the secondary amine has (R) -form.

In order to prepare tamsulosin, the steric purity of the R-type aromatic sulfonamide derivative of Formula 2 directly affects the steric purity and the amount of impurities in the final product, and the higher the steric purity, the better the purity of the final product.

In the method disclosed in Korean Patent Publication No. 1996-3810, to synthesize the aromatic sulfonamide derivative, a stereoisomer is synthesized through reductive amination reaction with an aromatic chitone of a sterically pure phenylamine derivative as shown in Scheme 1 below. (The result of the stereoselective reactivity of the optical phenylamine derivative is used.) This is again a dealkylation reaction using a palladium catalyst to finally synthesize an aromatic sulfonamide derivative.

Scheme 1

However, as a result of performing the process according to the Republic of Korea Patent Publication No. 1996-3810, the reaction starting material uses expensive three-dimensional pure methylbenzylamine, and the two metal catalysts (PtO ₂ and Pd) used in the entire process are very expensive. Due to the low economic feasibility for commercial production, the use of toxic hydrochloric acid and hydrogen, a dangerous gas for explosion, poses a great risk to commercial production, and the reaction process is complicated and time-consuming because it has to go through four stages of reaction. It takes a long time and is not suitable for commercial production.

In addition, according to the method described in Japanese Patent Application Laid-Open No. 58-18353, the aromatic sulfonamide derivative can be synthesized by a multi-step synthesis process as in Scheme 2 below.

Scheme 2

However, when synthesizing the aromatic sulfonamide derivatives according to the method known in Japanese Patent Application Laid-Open No. 58-18353, in order to synthesize the salts of the aromatic sulfonamide derivatives, a total of six reaction steps must be performed, and each reaction step The yield of is very low, the yield of the final product is very low, and the yield of the isomer is less than half of the existing yield when using a material that is not sterically pure starting material, which increases the manufacturing cost further It is not suitable for application in actual commercial production process.

The present invention is to solve the above-described problems, an object of the present invention is to provide a method for producing an R-type aromatic sulfonamide derivative which can economically and safely produce a high-purity R-type aromatic sulfonamide derivative using optical splitting method To provide.

In order to achieve the above object, the present invention comprises the steps of (a) dissolving the racemic aromatic amide derivative of Formula 1 in a mixture of phosphate buffer solution and organic solvent; And (b) adding and stirring penicillin acrylates in a solution in which the racemic aromatic amide derivative is dissolved, to provide a method for preparing an R-type aromatic sulfonamide derivative of Formula 2 below.

[Formula 1]

[Formula 2]

Hereinafter, the present invention will be described in more detail.

Features of the present invention are to secure economics by using a new raw material racemic aromatic amide derivative of the following formula 1 without using expensive three-dimensional pure raw materials used in the existing process and three-dimensionally from such racemic derivatives In order to obtain a pure R-type aromatic sulfonamide derivative, an enzyme is used to improve the yield and steric purity.

[Formula 1]

The present inventors have provided a method of stereoselectively deamidating a racemic derivative having a lower cost than the conventional stereoselective synthesis methods of Schemes 1 and 2 to obtain a stereoscopically pure aromatic sulfonamide derivative salt having no deamidation reaction. Invented.

Among the penicillin acrylates that can be used to successfully proceed the asymmetric deamidation reaction for such a racemic compound, the enzyme of Altus Biologics (trade name: ChiroCLEC-EC) of the United States may be preferably used. The ChiroCLEC-EC is a catalyst in which penicillin acrylates are crosslinked into fine crystal phases. As the organic solvent used with the ChiroCLEC-EC, EtOAc or toluene is preferable.

In the method for preparing an R-type aromatic sulfonamide derivative of the present invention, as shown in Scheme 3, the prepared racemate amide derivative is first dissolved in a mixed solution of an appropriate amount of a phosphate buffer solution and an organic solvent to completely dissolve it. After dissolution is confirmed, the pH is raised to 8.0 using a basic aqueous solution. After allowing to stand for a suitable period of time, penicillin acrylase was added, and the reaction solution was closed well in a reactor so that the reaction solution was stirred at a very high speed. At this time, the reaction proceeds until the S-type derivative of the racemic aromatic sulfonamide derivative as a starting material is completely deamidated. Here, the time point at which the S-type derivative is completely deamidated is that the optical rotation value does not change.

If the reaction starting material is confirmed to disappear completely by HPLC or optical analysis, after separating the layers, the organic layer in which the R-type aromatic sulfonamide derivative is dissolved is concentrated under reduced pressure, which is then diluted in a mixed solution of an organic solvent and hydrochloric acid and refluxed for 10 hours. The solid produced by stirring is cooled and filtered to obtain an R-type aromatic sulfonamide derivative of Chemical Formula 2. At this time, it is preferable to further carry out the neutralization step by adding a base to remove residual hydrochloric acid.

Scheme 3

As a solvent of the racemic aromatic amide derivative of Formula 1, ethyl acetate, diethyl ether, isopropyl ether or a mixture thereof is preferable, and ethyl acetate may be more preferably used.

The amount of penicillin acrylates used in the reaction is preferably 0.05 to 1.0 equivalents and more preferably 0.1 equivalents to the weight of the racemic aromatic amide derivative as a reactant. If the amount of the penicillin acrylatease is less than 0.05 equivalent to the weight of the reactant racemic aromatic amide derivative, the reaction rate is slowed and the yield of the product is lowered. If the amount is more than 1.0 equivalent, there is a problem in economic efficiency.

As for the density | concentration of the aqueous solution of hydrochloric acid used for the deamide reaction process of an amide, 1-6 normal is preferable and 3 normal is more preferable. When the concentration of the hydrochloric acid solution is used less than 1 normal, the reaction time increases, and if the concentration exceeds 6 normal, there is a problem in that the purity and yield of the final product are lowered due to an increase in side reactions.

Three-dimensional purity of the three-dimensionally pure aromatic amide derivatives produced as a result of performing this process using the prepared racemate amide derivatives was 99.9% or more on average and showed a yield of 70% or more.

Advantages of the method for preparing the aromatic sulfonamide derivative of the present invention are firstly, the reaction step can be reduced to two stages, and the steric purity of the aromatic sulfonamide derivative of Formula 2, which is the final substance, can be obtained with high purity of 99.9% or more. The yield of the material was 70% or more, which was 2 to 10 times more effective than the conventional process (yield up to 85% or more until the salt of the final product was obtained), and also the manufacturing cost using a low-cost racemic starting material It was able to drastically reduce.

Hereinafter, preferred examples and comparative examples of the present invention are described. The following examples and comparative examples are described for the purpose of more clearly expressing the present invention, but the contents of the present invention are not limited to the following examples and comparative examples.

All raw materials and solvents used for the present invention used reagents manufactured and sold by Aldrich, USA, TCI, Japan, etc. without further purification. As penicillin acrylase in the present invention, ChiroCLEC-EC of Altus Biologics was used.

HPLC (High Resolution Liquid Chromatography) was used as an analytical instrument to confirm the purity and stereoisomer ratio of the final product. Detailed analytical conditions for the measurement are shown below.

HPLC Set (Waters 484 Set)

2.Column: YMC-Pack A-302 ODS (5 ㎛, 4.6 mm x 150 mm)

UV Detecting wavelength: 285 nm

4. Mobile phase: aqueous solution of K ₂ HPO ₄ (1.0 g) and KH ₂ PO ₄ (1.0 g) / methanol / tetrahydrofuran (65: 30: 5 v / v)

5. Concentration: 5 μl (dissolve 10 mg of analyte in 1 ml of mobile phase)

7. Flow rate: 1 ml / min

8. Column temperature: room temperature

(When the racemic aromatic amide derivative is analyzed under the analytical conditions, the aromatic sulfonamide derivative exhibits a residence time of about 7 minutes.)

Other processes are described in detail in the Examples and Comparative Examples below.

(Example)

N- (pen-acetyl) -5- (2-aminopropyl) -2-methoxybenzyl sulfonamide (N- (Phenacetyl) -5- (2-aminopropyl) -2-methoxybenzylsulfonamide) R using the (-) - Preparation of 5- (2-aminopropyl) -2-methoxybenzylsulfonamide (R-(-)-5- (2-aminopropyl) -2-methoxybenzylsulfonamide) HCl

50 g (R / S = 50/50) of N- (phenacetyl) -5- (2-aminopropyl) -2-methoxybenzylsulfonamide were diluted in 1 L of 0.1 N pH 8 phosphate buffer. The pH of the reaction solution was adjusted to 8 again with 10% NaOH and 3.6 g of ChiroCLEC-EC was added to the reactor. The reactor was completely closed and the reaction proceeded while maintaining a constant temperature of 25 ° C. The progress of the reaction was checked at intervals of 5 hours, and the reaction was terminated when the (S) -form derivative was completely deamidated. (The end point of the reaction was that the optical rotation value of the reaction solution was not changed. .)

The suspended solids were filtered, 1 L of ethyl acetate was added to the reaction solution, and the ethyl acetate layer was separated. The separated ethyl acetate layer was concentrated under reduced pressure to 200 ml, 200 ml of 6 N aqueous hydrochloric acid solution was added, and the reaction solution was heated to reflux for 18 hours. The reaction solution was cooled to near 0 ° C., stirred for 4 hours, and then the resulting crystals were filtered while maintaining stirring. The crystals were washed with diethyl ether and dried to give 14.5 g of the desired product R-(-)-5- (2-aminopropyl) -2-methoxybenzylsulfonamide HCl. (Yield: 85% (R-form 50% regarded as reactant), melting point: 277 ° C., [α] ²⁵ _D = -71 (c = 1.0, MeOH) and steric purity (by HPLC): 99.9%)

Preparation of R-(-)-5- (2-aminopropyl) -2-methoxybenzylsulfonamide from R-(-)-5- (2-aminopropyl) -2-methoxybenzylsulfonamide HCl

200 g of R-(-)-5- (2-aminopropyl) -2-methoxybenzylsulfonamide HCl were dissolved in 1400 ml of water and 500 ml of saturated potassium carbonate solution was added. After crystals were separated, the mixture was stirred for 2 hours at room temperature, the crystals were collected by filtration, and then recrystallized from 750 ml of water to recrystallize R-(-)-5- (2-aminopropyl) -2-methoxybenzylsulfone 142 g of amide were obtained. (Yield: 82%, Melting Point: 168 ° C., [α] ²⁵ _D = -17.2 (c = 1.0, MeOH) and Stereoscopic Purity (by HPLC): 100%)

(Comparative Example)

Synthesis of 2R, 1R-2-methoxy-5- [2- (1-methylbenzylamino) propyl] benzenesulfonamide hydrochloride

A mixture of 9.72 g of 5-acetonyl-2-methoxybenzenesulfonamide, 5 g of Raney nickel (wetting) and 200 ml of methanol was catalyzed at 58 to 60 ° C. for 20 hours under a pressure of 10 kgf / cm ² in a hydrogen atmosphere. (R / S ratio in the reaction solution: 92/8) Lani nickel was filtered at the end of the reaction, the filtrate was acidified by addition of an ethanol solution of hydrogen chloride and the solvent was distilled off under reduced pressure. 80 ml of acetonitrile was added to the residue to crystallize, and the resulting mixture was heated at reflux for 1 hour, and then cooled crystals were collected to collect crude 2R, 1R-2-methoxy-5- [2- (1-methyleneamino 11.8 g of) propyl] benzenesulfonamide hydrochloride was obtained. The optical purity of the crystal as R, R-isomer is 98.2%.

Water (5 ml) and acetonitrile (10 ml) were added to the obtained crude crystals, the resulting mixture was heated to a solution, and then crystallized by adding 220 ml of acetonitrile, and the mixture was heated at reflux for 30 minutes. After cooling, the crystals were collected by filtration. This operation cycle was repeated three times to give 8.31 g of pure crystals (yield: 54%, melting point: 235 ° C., [α] ²⁵ _D = -17.2 (c = 1.0, MeOH) and steric purity (by HPLC): 99.8%)

Preparation of (R)-(-)-5- (2-aminopropyl) -2-methoxybenzenesulfonamide hydrochloride

A theoretical volume of a mixture of 560 ml of a methanol solution containing 28 g of 2R, 1R-2-methoxy-5- [2- (1-methylbenzylamino) propyl] benzenesulfonamide hydrochloride and 2.8 g of 10% palladium / carbon The catalytic reduction was carried out at 45-50 ° C. under atmospheric pressure in a hydrogen atmosphere until hydrogen was consumed. The palladium / carbon catalyst was filtered off, the solvent was distilled off under reduced pressure, and the separated crystals were washed with acetone to give (R)-(-)-5- (2-aminopropyl) -2-methoxybenzenesulfonamide hydro 19.4 g of chloride were obtained (yield: 95%, melting point: 277 ° C, [a] ²⁵ _D = -71 (c = 1.0, MeOH) and steric purity (by HPLC): 99.8%).

As shown in the experimental results of the Examples and Comparative Examples, using the method of producing an aromatic sulfonamide derivative of the present invention it is possible to produce a high-purity aromatic sulfonamide derivative in a two-step process.

As described above, the present invention can reduce the various reaction stages to two stages, can obtain a three-dimensional purity of the final material with a high purity of 99.9% or more and the yield of the final material is 70% or more compared to the existing process 2 to 10 The use of double and inexpensive racemic starting materials can significantly reduce manufacturing costs.

Claims (3)

(a) dissolving the racemic aromatic amide derivative of Formula 1 in a mixed solution of a phosphate buffer solution and an organic solvent; And (b) adding and stirring penicillin acrylates to the solution in which the racemic aromatic amide derivative is dissolved Method for preparing an R-type aromatic sulfonamide derivative of Formula 2 comprising: [Formula 1] [Formula 2] The method of claim 1, The organic solvent is a method for producing an R-type aromatic sulfonamide derivative, characterized in that selected from the group consisting of ethyl acetate, diethyl ether and isopropyl ether. The method of claim 1, The penicillin acrylatease is used in the R-type aromatic sulfonamide derivative manufacturing method, characterized in that 0.05 to 1.0 equivalent to the weight of the racemic aromatic amide derivative.