KR101379383B1 - A process for preparing high purity of ⒮―Metoprolol - Google Patents

Abstract

The present invention relates to a method for preparing (S) -metoprolol, which is used as a blood pressure lowering agent, and more particularly, starting materials (R) -epichlorohydrin and 4- (2-methoxyethyl) phenol as chiral salen ( chiral salen) A new process for efficiently preparing high purity (S) -metoprolol by carrying out condensation reaction with inhibited racemization under very mild conditions, followed by epoxidation in the presence of a base and then condensation with isopropylamine. It is about.

Description

A process for preparing high purity of ⒮―Metoprolol}

The present invention relates to a method for preparing (S) -metoprolol, which is used as a blood pressure lowering agent, and more particularly, starting materials (R) -epichlorohydrin and 4- (2-methoxyethyl) phenol as chiral salen ( chiral salen) A new process for efficiently preparing high purity (S) -metoprolol by carrying out condensation reaction with inhibited racemization under very mild conditions, followed by epoxidation in the presence of a base and then condensation with isopropylamine. It is about.

(S) -Metoprolol, ie, (S) -1- [4- (2-methoxyethyl) phenoxy] -3- (isopropylamino) -2-propanol, represented by the following structural formula 1 As a known substance used as an antihypertensive agent, it shows a much improved pharmacological effect compared to metoprolol racemic body.

[Structural formula 1]

Looking at the manufacturing method of (S) -metoprolol known in the prior art, first domestic patent registration No. 10-0332399 (date of registration; 2002.04.01.) Is a metoprolol racemate in the optical isomerization reagent menthyl chloroformate (Menthyl chloroformate )

A method of preparing a diastreomer, separating and hydrolyzing it by HPLC, to obtain a metoprolol enantiomer is introduced. However, such a method requires expensive equipment and a large amount of solvent in a separation process using HPLC, and at the same time, it requires a relatively long time, making it difficult to apply to commercial production in large quantities.

In addition, Tetrahedron 2007, 63, 1872 specifies a method for optically splitting an intermediate racemic epoxide using Jacobson's catalyst, as shown in Scheme A below. However, in the above method, the yield of the optical splitting process is very low, which is 50% or less, so that the overall yield is inevitably low. Also, since the racemization occurs in the methylation process of the hydroxy group thereafter, this method is also easy to apply commercially. not.

[Reaction Scheme A]

U.S. Patent No. 4,956,284 (registration date; September 11, 1990) discloses an optically selective epoxidation of an allyl ether group of intermediate 4- (2-methoxyethyl) phenyl allyl ether using microorganisms to convert to glycidyl ether groups. From this intermediate, a method for producing the (S) type optical isomer of the target substance is introduced. This method has an environmentally friendly advantage using microorganisms, but it takes a lot of time for microbial cultivation and intermediate separation process, and has a very low productivity.

In addition, US Patent No. 5,034,535 (registration date; July 23, 1991) introduces a method for preparing (S) -metoprolol through a five-step reaction process as shown in Scheme B below. Although this method is relatively easy in overall process, there is a problem of using expensive compounds at each step. Especially, since impurities are generated in the reaction process and the overall yield is only about 33%, development of more economical manufacturing method is difficult. Required.

[Scheme B]

Finally, U. S. Patent No. 5,362, 757 (registration date; Nov. 8, 1994) introduces a preparation method as in Scheme C, which is a three-step reaction process, which is more efficient than the other preparation methods described above. However, there is room for improvement in that the manufacturing cost is too high because expensive S-glycidol is used as a starting material.

[Scheme C]

1. Domestic Patent Registration No. 10-0332399 (Registration Date; 2002.04.01.) 2. U.S. Patent No. 4,956,284 (Registration Date; 1990.09.11.) 3. US Patent No. 5,034,535 (Registration Date; July 23, 1991) 4. U.S. Patent No. 5,362,757 (Registration Date; 1994.11.08.)

Tetrahedron 2007, 63, 1872

Therefore, the problem to be solved by the present invention is a method for preparing (S) -metoprolol and its salts used as a therapeutic agent for hypertension, in a milder reaction conditions using a more economical starting material to improve the problems of the conventional methods described above It is to provide a new manufacturing method that can obtain a high-purity target material optically with high efficiency.

The inventors of the present invention while trying to achieve the above problems, while using a commercially available (R) -epichlorohydrin [(R) -epichlorohydrin] as a starting material, in the presence of a chiral salen catalyst The present invention has been completed by developing a new process that minimizes the generation of impurities by inhibiting racemization side reactions .

In the present invention, in preparing (S) -metoprolol, CmHnXo ( C is carbon, H is hydrogen, X represents a halogen element, m is 1 to 4, n is 2 to 8, o is 1 to 2. ) Aliphatic solvent of CmHnXo ( C is carbon, H is hydrogen, X is halogen element, m is 6-8, n is 2-5, o is 1-2 ), aromatic solvent, acetone, ethyl ether, (R) -Epichlorohydrin under a chiral salen catalyst in any one solvent or two or more mixed solvents selected from isopropyl ether, methyl t-butyl ether, normal propyl ether, ethyl acetate, hexane and heptane. Reacting 4- (2-methoxyethyl) phenol to produce (R) -1- [4- (2-methoxyethyl) phenoxy] -3-chloro-2-propanol;

Aliphatic solvent of water, alcohol, CmHnXo ( C is carbon, H is hydrogen, X is halogen, m is 1-4, n is 2-8, o is 1-2 ), CmHnXo ( C is carbon , H represents hydrogen, X represents a halogen element, m is 6 to 8, n is 2 to 5, o is 1 to 2. Aromatic solvent, acetone, ethyl ether, isopropyl ether, methyl t-butyl ether , (R) -1- [4- (2-methoxyethyl) phenoxy] -3-chloro-2-propanol as a base in any one solvent or two or more mixed solvents selected from normal propyl ether and ethyl acetate. Reacting with a compound to obtain (S) -2-{[4- (2-methoxyethyl) phenoxy] methyl} oxirane;

The (S) -2-{[4- (2-methoxyethyl) phenoxy] methyl} oxirane is reacted with isopropylamine in an alcohol solvent having 1 to 4 carbon atoms to give (S) -1- [4- ( Step III obtaining 2-methoxyethyl) phenoxy] -3- (isopropylamino) -2-propanol; And a control unit.

The present invention provides a very economical method for producing (S) -metoprolol with high purity, which has a significantly superior pharmacological effect compared to metoprolol racemate.

That is, in the present invention, by using (R) -epichlorohydrin, which is commercially available at low cost, as a starting material, and efficiently inhibiting racemization side reactions using a chiral salen catalyst, a high-purity target material at a low manufacturing cost There is an effect that can be obtained.

In addition, the present invention has the effect of obtaining the target material in an environmentally friendly manner by using a small amount of reaction solvent under very mild conditions.

(S) -Methoprolol and its salt production method according to the present invention can be represented by the following scheme 1.

[Reaction Scheme 1]

Salts of (S) -metoprolol in the present invention include all pharmaceutically acceptable salts, but are particularly preferred tartrate, succinate or fumarate.

Hereinafter, the present invention will be described in detail with reference to Scheme 1 in each step. However, the number in the structural formula () to refer to each compound means the number of the structural formula shown in the above Scheme 1.

I stage; (R) - Epichlorohydrin and  4- (2- Methoxyethyl Phenolic Condensation reaction

First, (R) -epichlorohydrin and 4- (2-methoxyethyl) phenol of formula (4), which are starting materials, are used as chiral salen, organo-bimetallic catalyst (US 6,884,750, EP 1,292,602) in an organic solvent. ) To condensation reaction to prepare (R) -1- [4- (2-methoxyethyl) phenoxy] -3-chloro-2-propanol of formula (5).

At this time, the organic solvent used as the reaction solvent of CmHnXo ( C is carbon, H is hydrogen, X represents a halogen element, m is 1 to 4, n is 2 to 8, o is 1 to 2. ) Aliphatic solvent, CmHnXo ( C is carbon, H is hydrogen, X is halogen element, m is 6-8, n is 2-5, o is 1-2 ), acetone, ethyl ether, iso Any single solvent or a mixture of two or more solvents selected from propyl ether, methyl t-butyl ether, normal propyl ether, ethyl acetate, hexane, heptane may be used, of which dichloromethane, dichloroethane, toluene or chlorobenzene are reacted. It is preferable to use it as a solvent.

In addition, the amount of the organic solvent may be used in a volume ratio of 0.5 to 20 times with respect to (R) -epichlorohydrin of the structural formula (4) as a starting material, preferably 0.5 to 2 times.

In addition, the condensation reaction can be carried out at a temperature of 0 ~ 60 ℃, it is preferable to proceed at a mild temperature of 5 ~ 25 ℃, the reaction time can be carried out for 0.5 to 20 hours, to proceed to 0.5 to 7 hours It is preferable. If it is out of the range of the reaction temperature and the reaction time, the production of impurities may increase, resulting in a decrease in yield.

The chiral salen catalyst is represented by the following Structural Formula 2, the amount of the use may be 0.1 mol% or more, preferably 0.3 to 0.5 mol% may be used. The chiral salen catalyst is a catalyst developed by the present applicant, and is known in Korean Patent Registration No. 319045 (registration date; Dec. 14, 2001), and the like, and has a novel structural feature called a nonmetallic chiral salen catalyst. Have This structural feature facilitates catalyst recovery after use, maintains the same catalytic activity without a catalytic activity regeneration process, and thus can be reused repeatedly, and also has the function of preparing high purity optical purity compounds.

[Structural formula 2]

II  step; Epoxidation  reaction( Epoxidation )

Next, the crude compound of formula (5) is reacted with a base compound in water and an organic solvent to give (S) -2-{[4- (2-methoxyethyl) phenoxy] methyl} oxy of the formula (6). A column is obtained, and the crude structural formula (6) compound is distilled to obtain a high purity structural formula (6) compound.

At this time, the reaction solvent is aliphatic of water, alcohol, CmHnXo ( C is carbon, H is hydrogen, X represents a halogen element, m is 1 to 4, n is 2 to 8, o is 1 to 2). Solvent, CmHnXo ( C is carbon, H is hydrogen, X is halogen element, m is 6-8, n is 2-5, o is 1-2 ), acetone, ethyl ether, isopropyl Any single solvent selected from ether, methyl t-butyl ether, normal propyl ether, ethyl acetate or two or more mixed solvents may be used, but dichloromethane is preferably used as a reaction solvent.

And the amount of the reaction solvent may be used 1 to 10 times the volume ratio with respect to the compound of formula (5), preferably 1.5 to 3 times.

Examples of the base compound include potassium hydroxide, sodium hydroxide, potassium triphosphate (K ₃ PO ₄ ), sodium triphosphate (Na ₃ PO ₄ ), potassium hydrogen carbonate, sodium hydrogen carbonate, and the like, of which sodium hydroxide is preferable. The base compound may be used in an amount of 1 to 3 times the molar ratio with respect to the compound of formula (5), and preferably 1.0 to 1.5 times the amount. Moreover, reaction temperature can be made to react at 0-60 degreeC, and it is preferable to advance at 5-25 degreeC.

III  step; (S) - Metoprolol  Preparation of base

Next, the compound of formula (6) and isopropylamine are reacted and concentrated to form (S) -methoprolol base of formula (1), that is, (S) -1- [4- (2-methoxyethyl) phenoxy ] -3- (isopropylamino) -2-propanol is prepared. Although this reaction may proceed without a solvent, it is preferable to use the C1-C4 alcohol solvent, It is preferable to use isopropanol especially, You may use it, mixing with water. The amount of the alcohol solvent may be used 1 to 10 times, preferably 1 to 2 times.

In addition, the isopropylamine may be used 2 to 10 times the molar ratio with respect to the compound of formula (6), preferably 4 to 6 times. And, the reaction temperature may proceed at a temperature of 20 ~ 90 ℃, it is preferable to proceed at 80 ~ 85 ℃ in terms of reaction rate.

IV  step; (S) - Metoprolol  Manufacture of salt

Finally, the (S) -metoprolol and the pharmaceutically acceptable organic acid are reacted in alcohol, acetone, a mixed solvent thereof, or a mixed solvent in which water is added thereto to obtain a high-purity S-methoprolol salt in a solid state. .

In this case, the reaction solvent may be a C1-C4 alcohol or a single solvent of acetone, or a mixed solvent thereof, or may be a solvent in which water is mixed with the single solvent or a mixed solvent. Preferably isopropanol single solvent in terms of convenience and efficiency of recovery, the amount is preferably 4 to 10 times, preferably 4 to 6 times by volume relative to the compound of formula (1).

As the organic acid, any pharmaceutically acceptable organic acid may be used, but preferably, tartaric acid, succinic acid or fumaric acid may be used, and the amount of the organic acid is 0.5 to 1.0 times the molar ratio of the compound of Formula (1). Good to do.

Hereinafter, preferred examples are provided to aid in understanding the present invention. However, the scope of the present invention is not limited by these examples.

Example 1 ; Preparation of (R) -1- [4- (2-methoxyethyl) phenoxy] -3-chloro-2-propanol (Structure 5)

600 g (3.942 mol) of 4- (2-methoxyethyl) phenol was added to 300 mL of dichloromethane, and 437.7 g (4.731 mol) of (R) -epichlorohydrin was added thereto, followed by cooling to 5 to 10 ° C. 26.2 g (0.0197 mol) of R-form Salen catalyst are slowly added and stirred at 10 ° C. for 7 hours.

After completion of the reaction, dichloromethane was distilled under reduced pressure, 600 mL of methanol and 13.9 g (0.0789 mol) of L-ascorbic acid were added, followed by stirring at room temperature for 2 hours, followed by filtration using celite. The filtrate was concentrated to quantitatively obtain (R) -1- [4- (2-methoxyethyl) phenoxy] -3-chloro-2-propanol of formula (5).

Example 2 ; Preparation of (S) -2-{[4- (2-methoxyethyl) phenoxy] methyl} oxirane (Structure 6)

1047.0 g (4.278 mol) of (R) -1- [4- (2-methoxyethyl) phenoxy] -3-chloro-2-propanol are added to 2094 mL of dichloromethane, and cooled to 5 to 10 ° C. 205.4 g (5.134 mol) of sodium hydroxide was added thereto, and the temperature was gradually increased, followed by stirring at room temperature for 3 hours.

After the reaction was completed, the mixture was cooled to 5-10 ° C., 500 mL of dichloromethane was further added, and the organic layer was washed three times with 4 L of water. The organic layer was treated with anhydrous magnesium sulfate, filtered, and the filtered solution was concentrated under reduced pressure, and then distilled and purified to obtain (S) -2-{[4- (2-methoxyethyl) phenoxy] methyl of the formula (6). } 735.0 g (yield 89.5%) of oxirane was obtained.

Example 3 ; Preparation of (S) -Metoprolol Base

866.8 g (4.163 mol) of the above-mentioned (S) -2-{[4- (2-methoxyethyl) phenoxy] methyl} oxirane was placed in 867 mL of isopropanol, and 1476.4 g (24.977 mol) of isopropylamine was added thereto. After stirring for 4 hours at reflux.

Concentration under reduced pressure after the reaction was completed yielded quantitatively (S) -metoprolol base, that is, (S) -1- [4- (2-methoxyethyl) phenoxy] -3- (isopropylamino) -2-propanol.

1) Chemical Purity = 99.7%

2) optical purity = 99.8%

3) 1 H NMR (CDCl 3): 7.15 (2H, d, J = 8.4 Hz), 6.84 (2H, d, 8.4 Hz), 3.99 (1H, m), 3.95 (2H, m), 3.56 (2H, t, J = 7.2 Hz), 3.35 (3H, s), 2.86 (1H, dd, J = 3.6, 12.0 Hz), 2.82 (3H, m), 2.71 (1H, dd, J = 7.8 Hz, 12.0 Hz), 1.08 (6H, d, J = 6.6 Hz)

Example 4 ; Preparation of (S) -Metoprolol Tartrate

173.5 g (0.649 mol) of the above-mentioned (S) -1- [4- (2-methoxyethyl) phenoxy] -3- (isopropylamino) -2-propanol was added to 867 mL of isopropanol, and the temperature was raised to 60 to 70 ° C. After stirring for 1 hour, 54.1 g (0.360 mol) of L-tin acid is added thereto and stirred for about 30 minutes.

It was then cooled to 25 ~ 30 ℃ stirred for 1 hour, the precipitated crystals were filtered, washed with isopropanol and acetone, and dried in vacuo at 40 ℃ 19S (meth) propanol tartaric acid salt in solid form (yield 92.0%) )

1) Chemical Purity = 100%

2) optical purity = 99.8%

3) 1 H NMR (CDCl ₃ ): 7.06 (4H, d, J = 9.0 Hz), 6.77 (4H, d, J = 8.4 Hz), 4.45 (2H, m), 4.39 (2H, s), 3.98 (2H , dd, J = 4.2, 9.6 Hz), 3.88 (2H, dd, J = 5.4, 9.6 Hz), 3.52 (4H, t, J = 7.2 Hz), 3.33 (6H, s), 3.30 (2H, m) , 3.05-3.14 (4H, m), 2.78 (4H, t, J = 6.6 Hz), 1.32 (6H, d, J = 6.6 Hz), 1.29 (6H, d, J = 6.6 Hz)

Example 5 ; Preparation of (S) -Metoprolol Succinate

173.5 g (0.649 mol) of the above-mentioned (S) -1- (4- (2-methoxyethyl) phenoxy) -3- (isopropylamino) -2-propanol was added to 867 mL of isopropanol, and the temperature was raised to 60 to 65 ° C. After stirring for 1 hour, 39.5 g (0.340 mol) of succinic acid is added thereto and stirred for about 30 minutes.

Then cooled to 25 ~ 30 ℃ stirred for 1 hour, the precipitated crystals were filtered, washed with isopropanol and acetone, dried under reduced pressure at 40 ℃ to give a solid (S)-metoprolol succinate 181.5g (85.7% yield) )

1) Chemical Purity = 99.7%

2) optical purity = 99.8%

3) 1 H NMR (CDCl ₃ ): 7.90 (6H, bs), 7.10 (4H, d, J = 8.4 Hz), 6.81 (4H, d, J = 8.4 Hz), 4.31 (2H, m), 4.00 (2H , dd, J = 4.8, 9.6 Hz), 3.92 (2H, dd, J = 5.4, 9.6 Hz), 3.55 (4H, t, J = 7.2 Hz), 3.34 (6H, s), 3.17 (2H, m) , 3.10-2.95 (4H, m), 2.81 (4H, t, J = 6.6 Hz), 2.50 (4H, s), 1.27 (6H, d, J = 6.6 Hz), 1.25 (6H, d, J = 6.6 Hz)

Claims (5)

CmHnXo ( C is carbon, H is hydrogen, X is halogen element, m is 1-4, n is 2-8, o is 1-2. ) Aliphatic solvent, CmHnXo ( C is carbon, H is hydrogen , X represents a halogen element, m is 6-8, n is 2-5, o is 1-2, a ) aromatic solvent, acetone, ethyl ether, isopropyl ether, methyl t-butyl ether, normal propyl ether , (R) -epichlorohydrin and 4- (2-methoxyethyl) phenol in a single solvent selected from ethyl acetate, hexane, heptane or two or more mixed solvents under a chiral salen catalyst. I to prepare (R) -1- [4- (2-methoxyethyl) phenoxy] -3-chloro-2-propanol;
Aliphatic solvent of water, alcohol, CmHnXo ( C is carbon, H is hydrogen, X is halogen, m is 1-4, n is 2-8, o is 1-2 ), CmHnXo ( C is carbon , H represents hydrogen, X represents a halogen element, m is 6 to 8, n is 2 to 5, o is 1 to 2. Aromatic solvent, acetone, ethyl ether, isopropyl ether, methyl t-butyl ether , (R) -1- [4- (2-methoxyethyl) phenoxy] -3-chloro-2-propanol as a base in any one solvent or two or more mixed solvents selected from normal propyl ether and ethyl acetate. Reacting with a compound to obtain (S) -2-{[4- (2-methoxyethyl) phenoxy] methyl} oxirane;
The (S) -2-{[4- (2-methoxyethyl) phenoxy] methyl} oxirane is reacted with isopropylamine in an alcohol solvent having 1 to 4 carbon atoms to give (S) -1- [4- ( Step III obtaining 2-methoxyethyl) phenoxy] -3- (isopropylamino) -2-propanol;
Method for producing (S) -metoprolol, characterized in that it comprises a.
The method of claim 1, wherein the reaction solvents of steps I and II are dichloromethane, dichloroethane, toluene or chlorobenzene.
The method of claim 1 or 2, wherein the steps I and II are (S)-the method for producing metoprolol, characterized in that proceeds at a temperature of 5 ~ 25 ℃.
The method according to claim 1 or 2, wherein the amount of the chiral salen catalyst used in the step I is 0.3 to 0.5 mol%.
According to claim 1 or 2, wherein the base compound of step II is potassium hydroxide, sodium hydroxide, potassium triphosphate (K ₃ PO ₄ ), sodium triphosphate (Na ₃ PO ₄ ), potassium hydrogen carbonate, sodium hydrogen carbonate Method for producing (S)-metoprolol, characterized in that using at least one selected.