JPH045026B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel method for producing optically active oxazolidin-2-one derivatives, which inverts the configuration of an optically active epoxy compound and converts it into an oxazolidone ring. For more details, see the general formula [* indicates an asymmetric carbon. R ₁ represents a C ₁ to C ₄ lower alkyl group. R ₂ is a C ₁ to C ₄ lower alkyl group,
Indicates a benzyl group or a substituted benzyl group. ] The general formula is characterized in that an optically active epoxy compound represented by is reacted with an acid. [* indicates an asymmetric carbon. R ₁ represents a C ₁ to C ₄ lower alkyl group. ] The present invention relates to a method for producing an optically active 5-hydroxymethyl-N-substituted oxazolidin-2-one in which the configuration of the starting material is inverted. It is known that optically active 5-hydroxymethyl-N-substituted oxazolidin-2-ones having the (S) configuration are useful synthetic intermediates for optically active β-receptor blockers. It is being Regarding the substituent for N, isopropyl group and t-butyl group are important from the viewpoint of medicinal efficacy. The applicant of the present invention has already identified the above-mentioned useful optical activity 5.
-Hydroxymethyl-N-substituted oxazolidine-
Invented an enzymatic production method for 2-one (patent application 1982-
No. 141574 (Japanese Unexamined Patent Publication No. 59-31692), No. 57-141575 (Unexamined Japanese Patent Application No. 59-31693), No. 57-190585) (Unexamined Japanese Patent Application No. 59-31692)
59-78696). As shown in Formula 1, this is a method of optically resolving 5-acyloxymethyl-N-substituted oxazolidin-2-one in the (RS) form using an enzyme. The effective use of optical isomers having the opposite configuration to methyl-N-substituted oxazolidin-2-ones is of industrial importance. Hitherto, there have been no reports of an effective method for inverting the above-mentioned 5-hydroxymethyl-N-substituted oxazolidin-2-one to the desired optically active form, and even an effective racemization method has not been found. . The present inventors investigated this point and surprisingly found that when an epoxy compound derived from optically active 5-hydroxymethyl-N-substituted oxazolidin-2-one was treated with an acid, the asymmetric carbon At the same time as the configuration is reversed, the 5-hydroxymethyl-2-substituted oxazolidine-2- is converted into an oxazolidone ring and has the desired configuration at once.
The present invention was completed by discovering that on was generated. Specifically, the inversion method of the present invention is expressed as shown in Equation 2. (In the formula, * indicates an asymmetric carbon. _{R 1} and R ₂ are the same as above.) By using the effective inversion method according to the present invention, 5-hydroxymethyl having one desired configuration -N-substituted oxazolidin-2-one can be obtained in good yield from an N-substituted oxazolidin-2-one derivative in the (RS) form. Compound ( ) of the starting material for the inversion step in the present invention, that is, the general formula

The optically active epoxy compound represented by the formula (* indicates an asymmetric carbon; R ₁ and R ₂ are the same as above) is an optically active 5-hydroxymethyl-N- It is synthesized from optically active N-substituted aminopropanediol, which can be easily obtained by alkaline hydrolysis of substituted oxazolidin-2-one. A method for converting an optically active N-substituted aminopropanediol into an optically active epoxy compound (2) with retained configuration can be achieved by combining various known reactions. As an example, Equation 3 and Equation 4
Shown below. That is, as shown in Formula 3, an optically active N-substituted aminopropanediol is reacted with HBr-acetic acid,
Next, it is converted into an epoxy derivative using a base such as sodium methylate, and then the amino group is converted into a carbamate group using alkyl chlorocarbonate, benzyl chlorocarbonate, etc. to obtain an optically active epoxy compound (). In equation 4, p is substituted for HBr-acetic acid.
- It can be induced into an optically active tosylate with toluenesulfonyl chloride or the like, and then converted into an epoxy derivative similar to Formula 3 with a salt such as sodium methylate. In the step of converting these optically active N-substituted aminopropanediol into the epoxy compound of compound (), the configuration of the asymmetric carbon is maintained. The substituent R ₁ of the optically active epoxy compound ( ) which is the starting material for the inversion step in the present invention can be selected from C ₁ to C ₄ lower alkyl groups. Examples include methyl, ethyl, propyl, isopropyl, butyl, t-butyl groups, etc., and isopropyl and t-butyl groups are suitable as alkyl groups corresponding to highly effective β-receptor blockers. The substituent R ₂ of compound () is defined by the reagent used to convert an amino group into a carbamate group. As this reagent, methyl chlorocarbonate, ethyl chlorocarbonate, benzyl chlorocarbonate, or substituted benzyl chlorocarbonate can be used. Substituents corresponding to these
R ₂ is methyl, ethyl, benzyl and substituted benzyl groups. As the substituted benzyl group, p-
Substituted benzyl groups such as methoxybenzyl, p-nitrobenzyl, o-methoxybenzyl, o-nitrobenzyl and the like can be used. The substituent R ₂ of the amino group of the above-mentioned optically active epoxy compound () is a group that leaves in the inversion step, and industrially, R ₂ is preferably a methyl group or an ethyl group. By treating these optically active epoxy compounds () with an acid, they can be inverted and converted into 5-hydroxymethyl-N-substituted oxazolidin-2-ones. Acids used in the present invention include mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, and boric acid; formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, tartaric acid, citric acid, maleic acid, and fumaric acid. , benzoic acid, p-toluenesulfonic acid, and other organic carboxylic acids and organic sulfonic acids. Furthermore, so-called Lewis acid catalysts such as aluminum chloride, boron fluoride ether complex, zinc chloride, tin chloride, and iron chloride can also be used as the acid in the present invention. Solvents in this reaction include aromatic hydrocarbons such as benzene and toluene; alcohols such as methanol and ethanol; halogenated hydrocarbons such as methylene chloride and chloroform; dioxane,
Ethers such as ethyl ether and tetrahydrofuran; and polar solvents such as dimethyl formamide, dimethyl sulfoxide and acetonitrile can be used. Furthermore, water, which is industrially economical, can also be used. The reaction proceeds either homogeneously or heterogeneously, and the reaction temperature can be selected from room temperature to the reflux temperature of the solvent used. Preferably, the temperature ranges from room temperature to about 50°C. The amount of acid used in this reaction can range from a catalytic amount to about 10 times the amount of the optically active epoxy compound () as the substrate. When this reaction is carried out under these reaction conditions, the reaction can be completed within a range of several hours to 48 hours. After the reaction, the reaction solution can be made alkaline with an alkaline aqueous solution such as an aqueous sodium hydroxide solution, and the reactant can be extracted with an organic solvent such as methylene chloride or ethyl acetate. If the separated organic layer is concentrated under reduced pressure, the optically active 5-hydroxymethyl-N-substituted oxazolidin-2-one with the desired configuration reversed will precipitate as crystals. This makes it easier to obtain the target object. If necessary, it can be purified by recrystallization with a solvent such as ethyl acetate. Hereinafter, the present invention will be explained in detail with reference to Examples. Reference example 1 3.0 g of (5R)-3-t-butyl-5-hydroxymethyl-oxazolidin-2-one [α] ²⁰ _D = -44.7° (C = 1, CHCl ₃ ) was dissolved in 30 ml of 6N-NaOH, and 95 Stir at ℃ for 3 hours. After the reaction, the reaction solution is extracted with methylene chloride. Dry the methylene chloride layer with anhydrous magnesium sulfate. When methylene chloride is distilled off under reduced pressure, (R)-3-t-butyl-1,2-
2.4 g of white crystals of dihydroxypropane are obtained. Add 2.4 g of (R)-3-t-butylamino-1,2-dihydroxypropane to 40 ml of hydrogen bromide-acetic acid solution (25%) and stir at room temperature for 3 hours. After the reaction, the reaction solution is concentrated under reduced pressure to precipitate crystals.
The crystals are washed with ether to obtain 4.9 g of HBr salt of (R)-2-acetoxy-1-bromo-3-t-butylaminopropane. 2 g of HBr salt of (R)-2-acetoxy-1-bromo-3-t-butylaminopropane is dissolved in 10 ml of methanol, and 2.5 g of sodium methoxide (28% methanol solution) is added dropwise to this solution while cooling. 30 minutes after dripping
Stir for 1 minute. After the reaction, the reaction solution is concentrated under reduced pressure. water
Add 20ml and extract with methylene chloride. Dry the methylene chloride layer with anhydrous magnesium sulfate. When methylene chloride is distilled off under reduced pressure, a liquid of (R)-3-t-butylamino-1,2-epoxypropane is obtained. Dissolve the entire amount in 5 ml of methylene chloride,
Add 5 ml of water and add ethyl chlorocarbonate.
A solution of 0.8 g dissolved in 5 ml of methylene chloride and a solution of 1.1 g of potassium carbonate dissolved in 5 ml of water were simultaneously added dropwise under cooling and stirred at room temperature for 3 hours. After the reaction, add 10 ml of 2N-NaOH to the reaction solution and extract with methylene chloride. Dry the methylene chloride layer with anhydrous magnesium sulfate. When methylene chloride is distilled off under reduced pressure, (R)-N-ethoxycarbonyl-3-t-
Butylamino-1,2-epoxypropane 1.1g
of liquid. Reference example 2 (5R)-3-isopropyl-5-hydroxymethyl-oxazolidin-2-one [α] ²⁰ _D = -
57.6゜(C=1, CHCl ₃ ) 4.0g in 6N-NaOH30ml
Dissolve and stir at 90℃ for 3 hours. After the reaction, the reaction solution is extracted with methylene chloride. Dry the methylene chloride layer with anhydrous magnesium sulfate. When methylene chloride is distilled off under reduced pressure, (R)-3-isopropyl-1,
3.0 g of liquid 2-dihydroxypropane is obtained. 3.0 g of (R)-3-isopropyl-1,2-dihydroxypropane is dissolved in a solution containing 2.9 g of pyridine hydrochloride and 10 ml of pyridine. A solution of 4.4 g of para-toluenesulfonic acid chloride dissolved in 10 ml of methylene chloride is added dropwise to this solution while cooling. 5
Stir at room temperature for an hour. After the reaction, add 1.6 g of potassium carbonate to 50 ml of water. After removing excess pyridine from this solution under reduced pressure, potassium carbonate
Add 3.7g and extract with methylene chloride. Dry the methylene chloride layer with anhydrous magnesium sulfate. 4.3 g of p-toluenesulfonic acid was added to the solution from which magnesium sulfate had been removed by filtration, and methylene chloride was distilled off under reduced pressure to obtain crude (R)-1,2-dihydroxy-3-isopropylaminopropane-1-p-toluenesulfonate. 9.4 g of p-toluenesulfonate is obtained. Next, 5.8 g of the salt obtained by reconsolidating this salt with isopropyl alcohol was added to 50 g of methanol.
ml, and 5.2 g of sodium methoxide (28% methanol solution) is added dropwise to this solution while cooling. Stir for 30 minutes after addition. After the reaction, the reaction solution is concentrated under reduced pressure. Add 50ml of water and extract with methylene chloride. Dry the methylene chloride layer with anhydrous magnesium sulfate. When methylene chloride is distilled off under reduced pressure, (R)-
A liquid of 3-isopropylamino-1,2-epoxypropane is obtained. Dissolve the entire amount in 10 ml of methylene chloride, add 10 ml of water, and add a solution of 1.8 g of ethyl chlorocarbonate to 10 ml of methylene chloride and a solution of 2.2 g of potassium carbonate to 10 ml of water at the same time while cooling. and stir at room temperature for 3 hours. After the reaction, add 20 ml of 2N-NaOH to the reaction solution and extract with methylene chloride. Dry the methylene chloride layer with anhydrous magnesium sulfate. When methylene chloride was distilled off under reduced pressure, 1.8 g of liquid (R)-N-ethoxycarbonyl-3-isopropylamino-1,2-epoxypropane was obtained. Example 1 As shown in Reference Example 1, (5R)-3-t-butyl-5-hydroxymethyl-oxazolidine-2
(R)-N-ethoxycarbonyl-3-t obtained from -one [α] ²⁰ _D = -44.7° (C = 1, CHCl ₃ )
-butylamino-1,2-epoxypropane 1.1
Dissolve g in 10 ml of methylene chloride and add acetic acid to this solution.
Add 1.0g and stir at room temperature for 10 hours. After the reaction, add 10 ml of water to the reaction solution and make it alkaline with sodium hydroxide solution. Extract with methylene chloride. Dry the methylene chloride layer with anhydrous magnesium sulfate.
Crystals are obtained by distilling off methylene chloride under reduced pressure.
When washed with hexane, (5S)-3-t-
0.9 g of white crystals of butyl-5-hydroxymethyl-oxazolidin-2-one are obtained. [α] ²⁰ _D = +44.7° (C = 1, CHCl ₃ ) mp 83-84°C [Literature value: Chem.Pharm.Bull. 29 , (12), 3593
(1981) [α] ¹⁶ _D = -47.8° (C = 1, CHCl ₃ ) mp 83-84°C] ¹ H NMR (CDCl ₃ , 90MHz) δppm: 1.39 (9H, S, C (CH ₈ ) ₈ ) , 3.12~3.28 (1H, -OH), 3.43~3.95 (4H, _-CH2- CH- _CH2- O
−), 4.32 to 4.52 (1H,

[Formula]) Example 2 As shown in Reference Example 2, (5R)-3-isopropyl-5-hydroxymethyl-oxazolidin-2-one [α] ²⁰ _D = -57.6° (C = 1, CHCl ₃ )-N-ethoxycarbonyl-3 obtained from
Dissolve 1.8 g of -isopropylamino-1,2-epoxypropane in 20 ml of methylene chloride, add 1.6 g of acetic acid, and stir at room temperature for 10 hours. After the reaction,
Add 10 ml of water to the reaction solution and make alkaline with sodium hydroxide solution. Extract with methylene chloride. Dry the methylene chloride layer with anhydrous magnesium sulfate. Crystals are obtained by distilling off methylene chloride under reduced pressure. After washing with hexane, 1.4 g of white crystals of (5S)-3-isopropyl-5-hydroxymethyl-oxazolidin-2-one are obtained. [α] ²⁰ _D = +57.7° (C = 1, CHCl ₃ ) mp 56-57°C [Literature value: Chem.Pharm.Bull. 29 , (12), 3593
(1981) [α] ²¹ _D = +57.1° (C = 1.17, CHCl ₃ ) mp 55-56°C] ¹ H NMR (CDCl ₃ , 90MHz) δppm: 1.18 (6H, d, CHC (CH ₈ ) ₂ ), 3.30~4.20 (5H,

【formula】), 4.40~4.72 (1H,

[Formula]) Example 3 In the same manner as in Reference Example 1, (5R)-3-t-butyl-5-hydroxy-methyl-oxazolidine-
(R)-N-ethoxycarbonyl-3- obtained from 2-one [α] ²⁰ _D = -44.7° (C = 1, CHCl ₃ )
t-Butyl-amino-1,2-epoxypropane
Add 2.0g to 20ml of water and add 12N-HClml to this solution.
and stirred at room temperature for 5 hours. After the reaction, the reaction solution is made alkaline with sodium hydroxide solution and extracted with methylene chloride. Dry the methylene chloride layer with anhydrous magnesium sulfate. Crystals are obtained by distilling off methylene chloride under reduced pressure. When this is washed with hexane and collected, 1.5 g of white crystals of (5S)-3-t-butyl-5-hydroxymethyl-oxazolidin-2-one are obtained. [α] ²⁰ _D = +44.7° (C = 1, CHCl ₃ ) Example 4 In the same manner as in Reference Example 1, (5R)-3-t-butyl-5-hydroxymethyl-oxazolidine-2
(R)-N-ethoxycarbonyl-3-t obtained from -one [α] ²⁰ _D = -44.7° (C = 1, CHCl ₃ )
-butyl-amino-1,2-epoxypropane
Dissolve 2.0 g in 20 ml of ether, add 0.6 g of aluminum chloride to this solution, and stir at room temperature for 6 hours. After the reaction, the reaction solution is made alkaline with sodium hydroxide solution and extracted with methylene chloride. Dry the methylene chloride layer with anhydrous magnesium sulfate. Crystals are obtained by distilling off methylene chloride under reduced pressure. Wash this with hexane and take it out (5S)-3-
1.3 g of white crystals of t-butyl-5-hydroxymethyl-oxazolidin-2-one are obtained. [α] ²⁰ _D = +44.7° (C = 1, CHCl ₃ ) Example 5 In the same manner as in Reference Example 1, (5R)-3-t-butyl-5-hydroxymethyl-oxazolidine-2
(R)-N-ethoxycarbonyl-3-t obtained from -one [α] ²⁰ _D = -44.7° (C = 1, CHCl ₃ )
-butyl-amino-1,2-epoxypropane
Dissolve 2.0g in 20ml of ether and add citric acid to this.
Add 2.7 g and stir under reflux for 12 hours. After the reaction,
The reaction solution is made alkaline with sodium hydroxide solution and extracted with methylene chloride. Dry the methylene chloride layer with anhydrous magnesium sulfate. Crystals are obtained by distilling off methylene chloride under reduced pressure. When this is washed with hexane and removed, (5S)-3-t-butyl-
1.5 g of white crystals of 5-hydroxymethyl-oxazolidin-2-one are obtained. [α] ²⁰ _D = +44.7° (C = 1, CHCl ₃ ) Example 6 As shown in Reference Example 1, (5R)-3-t-butyl-5-hydroxymethyl-oxazolidine-
(R)-N-ethoxycarbonyl-3- obtained from 2-one [α] ²⁰ _D = -44.7° (C = 1, CHCl ₃ )
t-Butylamino-1,2-epoxypropane
Dissolve 2.0 g in 20 ml of methylene chloride, add 1 ml of concentrated sulfuric acid to this solution, and stir at room temperature for 4 hours. After the reaction, the reaction solution is made alkaline with sodium hydroxide solution and extracted with methylene chloride. Dry the methylene chloride layer with anhydrous magnesium sulfate. Crystals are obtained by distilling off methylene chloride under reduced pressure. When this was washed with hexane and removed, (5S)-3-t-butyl-5-hydroxymethyl-oxazolidine-2-
1.0 g of white crystals of . [α] ²⁰ _D = +44.7° (C = 1, CHCl ₃ ) Example 7 As shown in Reference Example 1, (5R)-3-t-butyl-5-hydroxymethyl-oxazolidine-
(R)-N-ethoxycarbonyl-3- obtained from 2-one [α] ²⁰ _D = -44.7° (C = 1, CHCl ₃ )
t-Butylamino-1,2-epoxypropane
Dissolve 2.0 g in 20 ml of methylene chloride, add 1 ml of boron trifluoride ethyl ether solution (47%), and stir at room temperature for 4 hours. After the reaction, the reaction solution is made alkaline with sodium hydroxide solution and extracted with methylene chloride. Dry the methylene chloride layer with anhydrous magnesium sulfate. Distillation of methylene chloride under reduced pressure yields a liquid. This was washed with hexane and crystallized to produce white crystals of (5S)-3-t-butyl-5-hydroxymethyl-oxazolidin-2-one.
0.8g is obtained. [α] ²⁰ _D = +44.7° (C = 1, CHCl ₃ )

Claims (1)

[Claims] 1. General formula [* indicates an asymmetric carbon. R ₁ represents a C ₁ to C ₄ lower alkyl group. R ₂ is a C ₁ to C ₄ lower alkyl group,
Indicates a benzyl group or a substituted benzyl group. ] The general formula is characterized in that an optically active epoxy compound represented by is reacted with an acid. [* indicates an asymmetric carbon. R ₁ represents a C ₁ to C ₄ lower alkyl group. ] A method for producing an optically active 5-hydroxymethyl-N-substituted oxazolidin-2-one in which the configuration of the starting material is inverted. 2. The manufacturing method according to claim 1, wherein R ₁ is a t-butyl group or an isopropyl group. 3. The manufacturing method according to claim 1 or 2, wherein R ₂ is a methyl group or an ethyl group. 4. The production method according to claim 1, wherein the acid is a mineral acid or an organic acid. 5. The manufacturing method according to claim 4, wherein the mineral acid is hydrochloric acid. 6. The manufacturing method according to claim 4, wherein the organic acid is acetic acid. 7. The production method according to claim 1, wherein the acid is a Lewis acid.