JPH0570452A - Production of optically active compound - Google Patents

Abstract

PURPOSE:To obtain optically active nipradilol which is a medicine for circulatory systems by reacting the corresponding optically active raw material in the presence of a quaternary ammonium salt, reacting the resultant compound with a thionyl halide, oxidizing the reaction product and successively reacting the obtained compound with isopropylamine and hydrous sulfuric acid. CONSTITUTION:For example, optically active 3,4-dihydro-8-hydroxy-3-nitroxy-2 H-1-benzopyran expressed by formula 1 is reacted with optically active glycidol expressed by formula 2 in the presence of a quaternary ammonium salt to provide optically active 3,4-dihydro-8-(2,3-dihydroxypropoxy)-3-nitroxy-2H-1- benzopyran expressed by formula 3, which is then oxidized with sodium m- periodate in the presence of ruthenium chloride. The resultant compound is then reacted with isopropylamine and further with hydrous sulfuric acid to afford optically active nipradilol expressed by formula 7. The method provides high yield throughout the process with hardly any racemization and is advantageous.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel process for producing optically active nipradilol useful as a circulatory drug.

[0002]

BACKGROUND OF THE INVENTION Nipradilol is represented by the following formula and is useful as a therapeutic agent for cardiovascular diseases such as hypertension and angina (Japanese Patent Publication No. 60-54317 and Japanese Patent Publication No. 1-53245). See the bulletin).

[Chemical 1]

Since this compound has an asymmetric carbon atom at the 3-position of benzopyran and at the 2-position of the side chain, four optical isomers, namely (2'S), (3R) -compound, (2 ')
The presence of S), (3S) -compounds, (2'R), (3R) -compounds and (2'R), (3S) -compounds,
It is known that they have different strengths of β-blocking action and vasodilatory action, so that they can be used properly according to the symptoms of the patient (Japanese Patent Laid-Open No. 60-208973).
(See the official gazette).

A known method for producing these optical isomers is via a glycidyl ether (for example, JP-A-60-208973 and JP-A-2-2566).
Nos. 72 and the like) all have drawbacks such as complicated reaction steps and low optical purity, and are difficult to carry out industrially. As the asymmetric synthesis method of the compound similar to the target compound of the present invention, the following method via diol is known, but it has drawbacks such as side reaction, racemization and low yield.

(1) Production of diol: J. Org. Chem. 51, 3710-3712
(1986)

[Chemical 2] According to this method, it is necessary to form a sodium salt of a phenolic body with sodium hydride, which is a strong inorganic base, and when a phenolic body weak to a base is used as a raw material as in the present invention, a side reaction is a problem. Becomes

Agric. Biol. Chem. Four
6 (5), 1153-1157 (1982).

[Chemical 3] Similar to the above method, this method has a problem of side reaction when a phenol body weak in base is used. The stated yield is also very low (52%).

JP-A-63-502585

[Chemical 4] This method also has a problem of side reaction similarly to the above two methods.

(2) Production of target product from diol: Chem. Pharm. Bull. 29 (12),
3593-3600 (1981)

[Chemical 5] According to this method, since the mesyl chloride or tosyl chloride to be used is not a highly selective reagent, diacyl products are considerably produced, and in addition to the desired monoacyl products, unnecessary monoacyl products (secondary secondary products) are produced. When the acyl derivative of alcohol) cannot be completely removed, the optical purity is deteriorated.

JP-A-63-502585

[Chemical 6] According to this method, aryloxypropanolamine can be obtained from a diol body in a short step, but it is necessary to remove a large amount of triphenylphosphine oxide, which is a by-product after chlorination, and the epoxy body production step has a strong basic condition. Since it is carried out under the conditions described above, there is a problem of side reaction when applied to a compound having an unstable skeleton under a strong basic condition such as the target compound of the present invention. Furthermore, this method has a low yield, which is problematic for industrial production.

Agric. Biol. Chem. Four
6 (5), 1153-1157 (1982).

[Chemical 7] The step of obtaining bromohydrin of this method is carried out under hydrogen bromide / acetic acid conditions, but in the application to the diol compound of the present invention having an electron-donating group in the aryl group,
This method cannot be used because a bromine group is introduced into the nucleus.

[0011]

The inventors of the present invention have conducted various studies in order to solve the above-mentioned drawbacks, and as a result, the method shown below is excellent in high yield and almost no racemization throughout the entire process. The inventors have found that it is a method for producing an optically active nipradilol, and completed the present invention.

The present invention provides an optically active 3,4-dihydro-
Optically active 3,4-dihydro-8- by reacting 8-hydroxy-3-nitrooxy-2H-1-benzopyran with an optically active glycidol in the presence of a quaternary ammonium salt.
(2,3-Dihydroxypropoxy) -3-nitroxy-2H-1-benzopyran is obtained, which is reacted with thionyl halide, and then oxidized with sodium metaperiodate in the presence of ruthenium chloride, and further isopropylamine is added. The present invention relates to a method for producing an optically active nipradilol, which comprises reacting with hydrous sulfuric acid after the reaction.

Of the present invention, for example, (2'R), (3
The formula of the method for producing R) -nipradilol is as follows.

[Chemical 8] The above reaction can be applied to the synthesis of other isomers by using the corresponding optically active raw material. That is, when the R-form of compound (1) and the S-form of compound (2) are used, (2'S), (3R) -nipradilol converts the S-form of compound (1) and the R-form of compound (2) into When used, (2 '
R), (3S) -nipradilol is the S of compound (1)
And the S-form of compound (2), (2'S), (3
S) -nipradilol is obtained.

The above reactions will be described in detail below by taking the (2'R) and (3R) forms as examples. (I) (3R) -3,4-dihydro-8-hydroxy-
When 3-nitroxy-2H-1-benzopyran (1) is reacted with (R) -glycidol (2) in the presence of a quaternary ammonium salt catalyst, 3,4-dihydro-8-[(2
R), 3-Dihydroxypropoxy]-(3R) -nitroxy-2H-1-benzopyran (3) is obtained. As the quaternary ammonium salt, tetra-lower alkyl ammonium halide is preferable, and tetrabutyl ammonium bromide is particularly preferable. The compound (3) is produced by reacting the compounds (1) and (2) with a catalyst in the presence or absence of a solvent for 0.5 to 10 hours at room temperature to 150 ° C. As the solvent, for example, tetrahydrofuran, dioxane, chloroform, ethyl acetate, acetone, acetonitrile, pyridine, dimethylformamide, dimethylsulfoxide, etc. can be used,
The reaction also proceeds by heating the mixture of the raw material compounds as they are. A usual method can be applied to the separation and purification of the reaction product.

(II) When the compound (3) is reacted with thionyl halide, a cyclic sulfite (4) is produced. As the thionyl halide used at this time, thionyl chloride is particularly preferable. The reaction can be carried out in a solvent in the presence or absence of a base. Examples of the solvent include halogenated hydrocarbons such as methylene chloride, carbon tetrachloride, chloroform, and ethylene chloride, as well as methyl acetate, tetrahydrofuran, dioxane, and the like. Examples of the base include triethylamine, pyridine, lutidine, and N.
-Organic amines such as methylpiperidine are used.
When using a base, the reaction is preferably carried out at a low temperature, particularly preferably under ice-water cooling. When no base is used, it is preferably carried out at 40 to 100 ° C. A usual method can be used to separate and purify the product.

(III) When the compound (4) is oxidized with sodium metaperiodate in the presence of a ruthenium chloride catalyst,
A cyclic sulfate (5) is obtained. As ruthenium chloride, ruthenium trichloride 1-3 hydrate is preferably used. The reaction proceeds by stirring the compound (4), the catalyst and the oxidizing agent in a solvent. As the solvent, a mixed solvent of acetonitrile-carbon tetrachloride-water is particularly preferable. The reaction is completed at a low temperature in a few minutes to a few hours. The product can be separated and purified by a usual method. In addition, the compound (4) can be directly subjected to the present reaction in the above-mentioned (II) without being separated and purified after synthesis under a reaction condition without using a base.

(IV) Compound (5) is reacted with isopropylamine and then reacted with sulfuric acid to obtain the desired (2'R), (3R) -nipradilol. The reaction between compound (5) and isopropylamine proceeds by stirring both compounds in a solvent at 10 to 100 ° C. for several minutes to several hours. After completion of the reaction, the produced compound is preferably used in the next step without isolation. That is, by adding hydrous sulfuric acid to the reaction mixture of the above reaction,
The target compound (7) can be obtained by further stirring at 1 to 100 ° C. for 1 to 10 hours.

[0018]

The present invention will be described in more detail below with reference to examples, but the present invention is not limited thereto.

Example 1 (a) 3,4-dihydro-8-[(2R), 3-dihydroxypropoxy]-(3R) -nitroxy-2H-1
-Preparation of benzopyran (3): (3R) -3,4-dihydro-8-hydroxy-3-nitrooxy-2H-1-benzopyran (1) 1.08 g, (R) -glycidol (2) 0.755 g and A mixture of 0.082 g of tetrabutylammonium bromide was heated and stirred at 65 ° C for 2 hours. The reaction mixture was dissolved in ethyl acetate, 1.5N N
After washing with aOH and then with saturated saline and drying over anhydrous sodium sulfate, the solvent is distilled off, and the residue is recrystallized from acetone-hexane to give the target compound (3) as colorless needles.
1.28 g (yield 87.7%) was obtained.

M. p. 131 ° C. [α] _n ²² + 14.1 ° (c = 0.83, MeOH) IR value: νmax, KBr, cm ⁻¹ 3489, 1640, 1633, 1277 ¹ H-NMR value: δ CD ₃ OD, ppm 2 _{.92-3.40 (2H, m, C 4} -H), 3.64
_{-3.72 (2H, m, CH 2} OH), 3.92-4.
_{10 (3H, m, OCH 2} CHOH), 4.18-4.
_{52 (2H, m, C 2} -H), 5.50-5.58
_{(H, m, C 3 -H} ), 6.66-6.75 (H, m,
Ar-H), 6.80-6.86 (2H, m, Ar-
H) Elemental analysis value: C H N calculated value as C ₁₂ H ₁₅ NO ₇ : 50.53 5.30 4.91 Measured value: 50.53 5.31 4.63

(B) 3,4-dihydro- (3R) -nitroxy-8-[[(4S) -2-oxo-4- (1,
3,2-Dioxathiolanyl)] methoxy] -2H-1
-Production of benzopyran (4): 1.00 g of the compound (3) obtained in (a) was suspended in 10 ml of methylene chloride, 1.42 g of triethylamine was added under stirring with ice water cooling, and then 0.63 g of thionyl chloride was added. A 1 ml solution of methylene chloride was added dropwise over 5 minutes. After reacting at the same temperature for 30 minutes,
Extraction was performed by adding ethyl acetate and saturated saline. The ethyl acetate layer was separated, washed with water and then saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated, the residue was purified by silica gel chromatography (chloroform), and a pale brown oily substance was obtained. Further, when recrystallized from ethyl acetate-hexane, 1.02 g of the target compound (4) as colorless needle crystals is obtained.
(Yield 87.8%) was obtained.

M. p. 111 to 113 ° C. [α] _D ²² -8.5 ° (c = 3.0, CHCl ₃ ) IR value: νmax, KBr, cm ⁻¹ 1620, 1486, 1277, 1208, 1110,
855 ¹ H-NMR value: δ CDCl ₃ , ppm 2.98-3.37 (2H, m, C ₄ -H), 3.98.
_{-4.58 (4H, m, CH 2} OAr and C 2 -
H), 4.67-5.02 (2H, m, CH ₂ OS
O ₂ ), 5.26-5.35 (1H, m, CHOS
_{O 2), 5.42-5.50 (1H,} m, C 3 -H),
6.74-6.92 (3H, m, Ar- H) Elemental analysis: C H N S Calculated as _{C 12 H 13 NO 8 S:} 43.51 3.95 4.23 9.68 Found: 43.58 4.09 4.23 9.74

(C) 3,4-dihydro-8-[[(4
S) -2,2-Dioxo-4- (1,3,2-dioxathiolanyl)] methoxy]-(3R) -nitroxy-2
Preparation of H-1-benzopyran (5): To a solution of 1.20 g of the compound (4) obtained in (b) in 12 ml of acetonitrile, 12 ml of carbon tetrachloride and 16 ml of water were added, and the mixture was stirred under ice-water cooling with stirring. Sodium iodate (1.55 g) and ruthenium trichloride trihydrate (5 mg) were added and the reaction was carried out for 1 hour. After the reaction, add water and chloroform for extraction,
The organic solvent layer was separated, washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was recrystallized from ethyl acetate-hexane to give 1.13 g (yield 89.8%) of the target compound (5) as colorless needle crystals.

M. p. 115 ° C. [α] _D ²¹ + 15.1 ° (c = 3.0, CHCl ₃ ) IR value: νmax, KBr, cm ⁻¹ 1630, 1483, 1388, 1280, 1213.
870 ¹ H-NMR value: δ CDCl ₃ , ppm 2.96-3.38 (2H, m, C ₄ -H), 4.24.
_{-4.50 (4H, m, CH 2} OAr and C 2 -
H), 4.73-4.92 (2H, m, CH ₂ OS
_{O 2), 5.22-5.34 (1H,} m, CHOS
_{O 2), 5.43-5.52 (1H,} m, C 3 -H),
6.77-6.93 (3H, m, Ar- H) Elemental analysis: C H N S Calculated as _{C 12 H 13 NO 9 S:} 41.50 3.77 4.03 9.23 Found: 41.54 3.88 4.05 9.11.

(D) 3,4-dihydro-8-[(2R)
-Hydroxy-3- (isopropylamino) propoxy]-(3R) -nitroxy-2H-1-benzopyran (7) [(2'R), (3R) -nipradilol]
Production: To a solution of 1.14 g of the compound (5) obtained in (C) in 17 ml of tetrahydrofuran was added 1.94 g of isopropylamine, and the mixture was stirred at room temperature for 30 minutes. The reaction product was concentrated under reduced pressure, the residue was dissolved in 30 ml of tetrahydrofuran, and then hydrous sulfuric acid (c.H ₂ SO ₄ , 2.5 ml:
2.3 g of H ₂ O, 1.0 ml) was added, and the mixture was stirred at room temperature for 2 hours. After potassium carbonate aqueous solution was added to adjust the pH to 9, most of tetrahydrofuran was distilled off under reduced pressure, and chloroform and water were added to the residue for extraction. The chloroform layer was separated, washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was subjected to alumina column chromatography (chloroform: methanol = 50: 1) to obtain a crude crystal of the target compound (7). This was recrystallized from ethyl acetate to give colorless needle crystals of pure product (0.99 g, yield 9
2.4%) was obtained.

Mp. 140.0 to 140.5 ° C. [α] _D ²² + 14.5 ° (c = 3.0, CHCl ₃ ) IR value: νmax, KBr, cm ⁻¹ 1617, 1485, 1279, 1219 ¹ H-NMR value: δ CDCl ₃ , ppm 1.09 (6H, d, J = 6.4 Hz, CH ₃ ×
2), 2.20-2.50 (2H, br s, NH a
nd OH), 2.70-2.91 (3H, m, CH ₂
NHCH), 2.94-3.35 (2H, m , C 4 -
H), 3.95-4.07 (3H, m, OCH ₂ C
H), 4.24-4.47 (2H, m , C 2 -H),
_{5.41-5.48 (1H, m, C 3} -H), 6.67
-6.90 (3H, m, Ar- H) Elemental _{analysis: C 15 H 22 N 2 O} 6 as C H N Calculated: 55.21 6.79 8.58 Found: 55.29 6.81 8.55

Example 2 Direct synthesis of compound (5) from compound (3): 1.00 g of compound (3) was suspended in 5 ml of chloroform, and 0.63 g of thionyl chloride under stirring in ice water was added to 1 m of chloroform.
After adding the 1 l solution, the mixture was heated under reflux at a bath temperature of 75 ° C for 40 minutes. The reaction solution was cooled with ice water, and after adding 4.5 ml of acetonitrile, 1.50 g of sodium metaperiodate, 10 mg of ruthenium trichloride trihydrate and 6 ml of water, 3 at the same temperature.
Stir for 0 minutes. After the reaction, water and chloroform were added to separate the organic solvent layer, and a dilute aqueous solution of sodium hydrogen sulfite,
Then, it was washed with brine and dried over anhydrous sodium sulfate.
The solvent was distilled off, and the residue was subjected to silica gel chromatography (chloroform) to obtain 1.02 g (yield 83.7%) of compound (5) as colorless crystals. The physical properties of the compound (5) obtained here were the same as those obtained in Example 1 (C).

Example 3 Direct synthesis of compound (7) from compound (5): To a mixed solvent solution of 0.60 g of compound (5) in 4.0 ml of methanol and 2.0 ml of tetrahydrofuran was added 308 mg of isopropylamine, and the mixture was stirred at room temperature for 1 hour. Stir for hours. After the reaction, hydrous sulfuric acid (cH ₂ SO ₄ , 2.5 ml: H ₂ O, 1.0 ml) 2.90
g was added and reacted at a bath temperature of 55 ° C. for 1 hour. After adding potassium carbonate aqueous solution to adjust the pH to 9, most of the organic solvent was distilled off under reduced pressure, and chloroform and water were added to the residue for extraction. The chloroform layer was separated, washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was subjected to alumina column chromatography (chloroform: methanol = 50: 1) to obtain a crude crystal of compound (7). When this product was recrystallized from ethyl acetate, 0.51 g (yield 90.4%) of pure pure colorless needles was obtained. Compound (7) obtained here
Had the same physical properties as those obtained in Example 1 (d).

Example 4 (3R) -3,4-dihydro-8-hydroxy-3-nitroxy-2H-1-benzopyran ( 1 ) with (S) -glycidol in the presence of tetrabutylammonium bromide as a catalyst. Reaction is carried out in the same manner as in (a) to give 3,4-dihydro-8-[(2S), 3-dihydroxypropoxy].
-(3R) -Nitroxy-2H-1-benzopyran was obtained. By applying the reactions of Examples 1- (b) to (d) thereto, (2'S), (3R) -nipradilol was obtained.

Mp. 105-105.5 ° C. [α] _D ²³ + 15.3 ° (c = 3.0, CHCl ₃ ) IR value: νmax, KBr, cm ⁻¹ 1630, 1486, 1276, 1220 ¹ H-NMR value: δ CDCl ₃ , ppm 1.08 (6H, d, J = 6.1 Hz, CH ₃ ×
2), 1.60-2.45 (2H, br s, NH a
nd OH), 2.70-2.92 (3H, m, CH ₂
NHCH), 2.94-3.36 (2H, m , C 4 -
H), 3.95-4.08 (3H, m, OCH ₂ C
H), 4.23-4.48 (2H, m , C 2 -H),
_{5.40-5.50 (1H, m, C 3} -H), 6.68
-6.90 (3H, m, Ar- H) Elemental _{analysis: C 15 H 22 N 2 O} 6 as C H N Calculated: 55.21 6.79 8.58 Found: 55.34 6.70 8.60

Claims (7)

[Claims] 1. An optically active 3,4-dihydro-8-hydroxy-3-nitroxy-2H-1-benzopyran is reacted with an optically active glycidol in the presence of a quaternary ammonium salt. -Dihydro-8- (2,3
-Dihydroxypropoxy) -3-nitroxy-2H-
1-benzopyran is obtained, which is reacted with thionyl halide, then oxidized with sodium metaperiodate in the presence of ruthenium chloride, further reacted with isopropylamine, and then treated with hydrous sulfuric acid. ,
Production method of optically active nipradilol. 2. Using (3R) -3,4-dihydro-8-hydroxy-3-nitroxy-2H-1-benzobenzopyran and (R) -glycidol, (2′R), (3
The method according to claim 1, wherein R) -nipradilol is produced. 3. Using (3R) -3,4-dihydro-8-hydroxy-3-nitroxy-2H-1-benzopyran and (S) -glycidol, (2'S), (3R)-
The production method according to claim 1, wherein nipradilol is produced. 4. The method according to claim 1, wherein the quaternary ammonium salt is a tetra-lower alkyl ammonium halide. 5. The method according to claim 1, wherein the quaternary ammonium salt is tetrabutylammonium bromide. 6. The method according to claim 1, wherein the thionyl halide is thionyl chloride. 7. Ruthenium chloride is ruthenium trichloride 1 to
The method according to claim 1, which is a trihydrate.