JPH0637449B2 - Process for producing optically active atenolol and its intermediates - Google Patents

Description

TECHNICAL FIELD The present invention relates to a method for producing atenolol, which is effective as a therapeutic agent for angina / arrhythmia / hypertension, and an optically active intermediate thereof. Atenolol has a particularly excellent pharmacological action among β blockers often used as a therapeutic drug for the above-mentioned symptoms, and is a drug of interest. It is generally known that β-blockers have an optically active form, and among them, S form has an effective pharmacological action.

(Prior Art) Conventionally, as a method for producing optically active atenolol, the following method using D-mannitol as a starting material is known (Japanese Patent Laid-Open No. 50-77331, DE 2453324).

( , Z represents a halogen or sulfonyloxy group, and * represents a non-carbon. (Problems to be Solved by the Invention) However, in this method, there are multiple steps in the synthesis of compound (III), and when the primary hydroxyl group of compound (III) is converted to a halogen or sulfonyloxy group, the reaction reagent and NH Optical reaction of the glycidyl ether (I) obtained by the reaction of ₂ COCH ₂ groups to produce a large amount of by-products converted to NCCH ₂ groups, the yield is 50% or less, and the reaction to secondary hydroxyl groups also occurs to some extent. The purity is as low as 44% ee, which is a method with little practicality.

In addition, the following method often used for the synthesis of optically active β-blockers (Ar 'represents an aryl group, X represents a leaving group, and * represents a non-carbon.) Aryloxyoxazolidin-2-one (V
The ring opening of I) requires strong conditions for alkaline hydrolysis, in which case NH ₂ COCH ₂ which is unstable under alkaline conditions.
It cannot be used in the synthesis of atenolol because the group decomposes.

(Means for Solving the Problems) In view of the above points, the present inventor diligently studied in order to obtain an efficient process for producing glycidyl ether (I) having high optical purity without causing racemization. As a result, the formula of optically active epichlorohydrin The present invention has been completed by finding that the above object can be sufficiently achieved by reacting the compound represented by the above formula at 0 to 45 ° C.

The present invention, in the presence of 1 to 1.5 times equivalent amount of alkali hydroxide to optically active epichlorohydrin in the temperature range of 1 to 45 ° C. in a water-containing solvent, A compound represented by the formula (I) characterized by reacting an optically active epichlorohydrin A method for producing a compound represented by (* represents non-carbon), and a method for producing an optically active atenolol (II) characterized by reacting compound (I) with isopropylamine. is there.

The water-containing solvent used in this reaction is selected from water or a mixture with the following organic solvent. That is, alcohols such as methanol, ethanol and isopropyl alcohol, ethers such as ether, tetrahydrofuran and dioxane, hydrocarbons such as hexane, heptane, benzene and toluene, halogenated hydrocarbons such as dichloromethane and dichloroethane, acetone and methyl ethyl ketone. An aprotic polar solvent such as a ketone, dimethylformamide, or dimethylsulfoxide may be added singly or as a mixture of two or more kinds to water, and it may be a homogeneous system or a heterogeneous system. When the reaction is carried out with an aqueous solvent, the desired optically active glycidyl ether (I) is precipitated as a solid, and therefore post-treatment is very simple and preferable. When the amount of the substrate or base to be charged to water is large, the raw material epichlorohydrin takes in the product (I) and becomes a viscous slurry liquid. Epichlorohydrin and (I) are dispersed, which makes it easier to stir. How much water to use 1 to 20 times the weight is suitable. If an organic solvent is added, it can be used in a ratio of 1: 1 to 0.0001 (V / V ratio) with respect to water. Further, in order to facilitate the precipitation of the product, appropriate amounts of sodium chloride, potassium chloride, sodium carbonate, potassium carbonate, magnesium sulfate and sodium sulfate may be added to the reaction system. As the alkali hydroxide, lithium hydroxide sodium hydroxide or potassium hydroxide is preferably used, and the amount thereof is 1 with respect to the optically active epichlorohydrin.
~ 1.5 times equivalent is appropriate.

Is appropriately 0.5 to 2.0 molar equivalents with respect to the optically active epichlorohydrin. The reaction is epichlorohydrin Even if added to the alkaline aqueous solution of It may be added to epichlorohydrin as a solid or aqueous solution of (M is an alkali metal). The reaction is preferably carried out in the temperature range of 0 to 45 ° C, more preferably 0 to 30 ° C.

Below 0 ° C, the reaction hardly occurs and water may freeze, which is not suitable. On the other hand, if it exceeds 45 ° C, the optical purity of the obtained glycidyl ether (I) is lowered and the proportion of by-products is increased, which is not preferable. In this reaction, the higher the reaction temperature, the more likely the racemization will occur, and the glycidyl ether (I) produced will be excessive. It may react with and give a by-product, so the initial value is 0
It is best to cool to 20 ° C and gradually raise the temperature. The lower the reaction temperature, the higher the optical purity of the glycidyl ether (I) formed, and the glycidyl ether (I) of 96% ee can be obtained by the reaction at 5 ° C. The reaction time may be 5 to 15 hours at room temperature and 10 to 48 hours at 5 ° C. However, if it is longer than that, it is difficult to give a fine solid substance and it is not preferable to react for a too long time. In order not to produce this by-product It is preferable to add 1 mol equivalent or more to the alkali. In this case, the product is glycidyl ether (I)
Besides halohydrin (VII) ( * Represents unsaid carbon. ) May be produced as a by-product, but this halohydrin (VII) can be mixed because it can be converted to atenolol (II) by reaction with isopropylamine.

As the reaction proceeds, the target glycidyl ether (I) precipitates as crystals, which can be filtered off, but can be extracted with ethyl acetate or the like if necessary.

The advantage of the method of the present invention is that the optically active glycidyl ether (I), which is a reaction product, is separated as a solid during the reaction, and there is no fear of mixing by-products in an operation such as extraction, An optically active glycidyl ether (I) excellent in both optical purity and chemical purity can be easily obtained.
As the optically active epichlorohydrin used in this reaction, epichlorohydrin having a high optical purity, which is obtained, for example, from Japanese Patent Application Laid-Open No. 61-132196, filed by the present applicant, can be used.

The optically active glycidyl ether (I) obtained here has an optical purity of 90 to 93% ee, and this is directly reacted with isopropylamine to give optically active atenolol (II), which is recrystallized or an optically active organic acid such as tartaric acid. , A salt with dibenzoyl tartaric acid, glutamic acid, etc., and may be purified by a diastereomer method, but the optically active glycidyl ether (I) is methanol, ethanol, isopropyl alcohol, n-butanol, t-butanol, hexanol, cyclohexanol. Such as lower alcohol having 1 to 6 carbon atoms, acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone, ketone having 1 to 6 carbon atoms such as cyclohexanone, methyl acetate,
One or more selected from organic acid esters such as ethyl acetate, ethyl butyrate and ethylene glycol diacetate, and alkyl nitrites having 1 to 4 carbon atoms such as acetonitrile, propionitrile, butyronitrile and isobutyronitrile. It is also possible to produce atenolol (II) having a high optical purity by purifying the product to an optical purity of 98% or more by recrystallization by using as a solvent, preferably alcohol or ketones as a solvent, and then reacting with isopropylamine. In particular, the optically active atenolol has a small solubility difference between the racemate and the optically active substance, and the operation is very complicated to increase the optical purity of the atenolol, so that the intermediate compound (I) is used.
It is desirable to purify at the stage.

The conversion of the optically active glycidyl ether (I) to the optically active atenolol (II) can be performed as follows. That is, the compound (I) is added to water or a lower alcohol such as methanol, ethanol, isopropyl alcohol, n
-Butanol or a mixed solvent thereof in isopropylamine 3 to 50 times mol, more preferably 5 to 30 times mol and 40 times
This can be achieved by heating and stirring at a temperature of -80 ° C for 5 to 20 hours. The amount of the solvent is the optically active glycidyl ether (I)
It can be appropriately selected so that the compound (I) is dissolved in the range of 3 to 100 ml per 1 g during the reaction to form a uniform solution.
When the compound (I) mixed with halohydrin (VII) is used, a base such as sodium carbonate, potassium carbonate, potassium hydroxide or sodium hydroxide is added to the halohydrin (VII) in an amount of 1 to 5 times from the beginning or the middle of the reaction. The desired optically active atenolol (II) can be obtained by adding an equivalent amount and carrying out in the same manner.

1-Aryloxy-3-amino-2-propanol derivatives have β-adrenergic blocking action, and most of them are used as racemates, but substantially only S form has an effective pharmacological action. Has been clarified by many studies, and it is considered that the S-form is particularly useful in the atenolol of the present invention.

(Effect of the Invention) According to the present invention, a target substance having a high optical purity can be easily obtained in a high yield by a simple reaction route without causing racemization as compared with the conventional method.

Hereinafter, the present invention will be described in more detail with reference to Examples.

(Example) Example 1 3.02 g (0.02 M) was dissolved in 0.96 g of NaOH and 9.69 g of H ₂ O, cooled to 3 ° C., and with stirring, ▲ [α] ²¹ _D ▼ -35.0 ° R.
1.85 g of-(-)-epichlorohydrin was added and stirred for 3 hours while returning to room temperature. The precipitated crystals are filtered off,
When washed with water and vacuum dried in the presence of phosphorus pentoxide, S-(+)
2.66 g of glycidyl ether (I) were obtained. (Yield 6
4%) mp 161-162 ° C ▲ [α] ²¹ _D ▼ + 9.6 ° (c = 1.0, methanol) (lit DE 2453324 mp 147-149 ° C ▲ [α] ²¹ _D ▼ + 4.8 ° (c = 1.0, Methanol)) NMR (DMSO-d ₆ ) δ: 2.65 to 2.73 (1H, m, CH) 2.83 (1H, dt, J = 1.1,5.1Hz, CH) 3.29 (2H, s, CH ₂ ) 3.33 (1H, m, CH) 3.80 (1H, ddd, J = -11.4,1.1,6.6Hz, CH) 4.29 (1H, ddd, J = -11.4,1.1,2.6Hz, CH) 6.82 (1H, br s, NH) 6.89 (2H, J = 7.7Hz, ArH) 7.17 (2H, d, J = 7.7Hz, ArH) 7.39 (1H, br s, NH) Example 2 In Example 1, R-(−)-epichlorohydrin Instead of using ▲ [α] ²¹ _D ▼ + 35.0 ° S-(+)-epichlorohydrin, the reaction was performed in exactly the same manner, and R-
2.88 g of (-)-glycidyl ether (I) was obtained. ▲
[Α] ²¹ _D ▼ −9.54 ° (c = 1.0, methanol) Example 3 20.09g (0.133M) 5.6g KOH, 50g water, 5g methanol
Let it run, ▲ [α] ²¹ _D ▼ + 34.2 ° S-(+)
-Drop epichlorohydrin 9.31 g under stirring at 11 ° C,
After the temperature was raised to 30 ° C. over 3 hours with stirring, the product was separated by filtration, washed with water, and vacuum dried in the presence of phosphorus pentoxide to give R-
(−)-Glycidyl ether (I) and halohydrin (VI
17.9 g of an approximately 1: 1 mixture of I) was obtained.

Yield 33.5% and 26.8%, respectively. Example 4 S-(+)-glycidyl ether (I) obtained in Example 1
After stirring 2.66 g in 24.8 g of methanol and 21.6 g of isopropylamine under reflux for 6 hours, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol 20: 1) to give S-(- ) -Atenolol (II) 3.04 g was obtained (yield 89%). The optical purity of this product was 93% ee when analyzed by HPLC using Chiralcel OD (trade name).

▲ [α] ²¹ _D ▼ -15.57 ° (c = 1.0, 1NHCl) mp15
1.0-152.5 ° C. (lit DE 2453324 ▲ [α] ²¹ _D ▼ -13.6 ° (c = 1.0, 1 NHCl), mp 151.3-153 ° C.) Example 5 R-(−)-glycidyl ether obtained in Example 3 (I)
8.77 g of a mixture of halohydrin and halohydrin (VII) in a ratio of about 1: 1 was stirred in 80 g of isopropylamine and 80 g of methanol with heating under reflux for 5 hours, ₃ g of Na ₂ CO ₃ was added, and the mixture was further heated with stirring for 2 hours. The reaction mixture was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to obtain 8.89 g of R-(+)-atenolol (II) (yield 85%). The optical purity of this product was 90% ee when analyzed by HPLC using Chiralcel OD (trade name).

▲ [α] ²¹ _D ▼ + 15.0 ° (c = 1.0, ¹ NHCl) mp 151.5-152.8 ° C. ¹ HNMR (DMSO-d ₆ ) δ: 0.99 (6H, d, J = 6.2Hz, CH ₃ ) 2.60〜 _{2.75 (2H, m, CH 2} ) 3.28 (2H, s, CH 2) 3.30~3.40 (1H, m, CH) 3.77~3.96 (3H, m, CH 2, CH) 6.80 (1H, brs, NH) 6.86 (2H, d, J = 7.7Hz, ArH) 7.17 (2H, d, J = 7.7Hz, ArH) 7.37 (1H, brs, NH) Example 6 S-(+)-glycidyl obtained in Example 1 When ether (I) is recrystallized from methanol, the melting point is 167.3 to 168.6.
The compound (I) having a temperature of ▲ [α] ²¹ _D ▼ + 10.8 ° (c = 0.5, methanol) was obtained. This was reacted with isopropylamine in the same manner as in Example 4 to obtain S-(−)-atenolol (II). The optical purity of this product is Chiralce
98.3% ee analyzed by HPLC using lOD (trade name)
Met.

Example 7 The R-(-)-glycidyl ether (I) obtained in Example 3 was recrystallized from acetone to give a melting point of 166.2 to 167.9 ° C.
A compound (I) of ▲ [α] ²¹ _D ▼ -10.6 ° (c = 0.5, methanol) was obtained. This was reacted with isopropylamine in the same manner as in Example 4 to obtain R-(+)-atenolol (II).

The optical purity of the compound (II) obtained here is Chiralcel OD.
It was 98.1% ee as analyzed by HPLC using (trade name).

Claims (4)

[Claims] 1. The formula in the presence of 1 to 1.5 equivalents of alkali hydroxide with respect to the optically active epichlorohydrin in a water-containing solvent at 0 to 45 ° C. A compound represented by the formula (I) characterized by reacting an optically active epichlorohydrin (* Represents a non-famous carbon.) 2. A method for producing an optically active atenolol, which comprises reacting the compound represented by the formula (I) obtained by the method according to claim 1 with isopropylamine. 3. The process according to claim 2, wherein the configuration of optically unreactive carbon of the optically active atenolol is S-configuration. 4. A process for producing atenolol having high optical purity, which comprises recrystallizing a compound represented by the formula (I) obtained by the method according to claim 1 using an organic solvent and then reacting it with isopropylamine. .