JPH0480896B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for inverting the configuration of optically active aminopropanediols.
For more details, see the general formula (In the formula, * represents an asymmetric carbon. R ¹ represents a C ₁ to _{C 4} lower alkyl group.) The optically active aminopropanediols represented by the general formula (In the formula, * represents an asymmetric carbon. ^{R 1} represents a C ₁ to C ₄ lower alkyl group. ^{R 2} represents a C ₁ to _{C 4} lower alkyl group, benzyl group, or substituted benzyl group. ) and then reacted with water or a basic aqueous solution, (In the formula, * represents an asymmetric carbon. R ¹ represents a lower alkyl group of C ₁ to C ₄ ). Regarding optically active N-substituted aminopropanediol, compounds having the (S) configuration are known to be useful synthetic intermediates for optically active β-receptor blockers. Regarding the substituent for N, isopropyl group and t-butyl group are important from the viewpoint of medicinal efficacy. Generally, when a compound having an asymmetric carbon is obtained by optical resolution or asymmetric hydrolysis, the optical isomer, which is not needed industrially, is racemized.
It is essential to have a method for reusing the optical isomer or preferably inverting the unnecessary optical isomer into the required optical isomer. Optically active N- represented by general formula ()
There have been no reports of an effective method for converting substituted aminopropanediol into a desired optically active form, and even an effective method for racemization has not been found. Furthermore, methods for converting the configuration of optically active 2-amino alcohols include JP-A-49-75545 and JP-A-55.
-20785 is known, but it could not be applied to optically active N-substituted aminopropanediol. The present inventors investigated this point and surprisingly found that when an epoxy compound derived from an optically active N-substituted aminopropanediol is treated with water or a basic aqueous solution, the configuration of the asymmetric carbon is reversed and at the same time The present invention was completed by discovering that N-substituted aminopropanediol having a desired steric configuration can be produced all at once. Specifically, the inversion method of the present invention is expressed as Equation 1. (In the formula, the symbols are the same as above) The compound ( ) of the starting material for the inversion step in the present invention, that is, the general formula

The optically active N-substituted aminopropanediol compound represented by [Formula] (symbols are the same as above) is disclosed in patent applications filed by the present applicant (Japanese Patent Laid-Open Nos. 59-31692, 59-31693, and 59-78696).
Optically active 5-hydroxymethyl-
It can be easily obtained by alkaline hydrolysis of N-substituted oxazolidin-2-one. Next, the method for converting into an optically active epoxy compound (2) with retained configuration can be achieved by combining various known reactions. For example, Equation 2 and Equation 3
This method is used. That is, as shown in Formula 2, 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 (2). In formula 3, p- instead of 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 2 with a base such as sodium methylate. In the process 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 ( ) used as the raw 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 preferred 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. The corresponding substituents R ₂ are methyl, ethyl, benzyl and substituted benzyl groups. As the substituted benzyl group, substituted benzyl groups such as p-methoxybenzyl, p-nitrobenzyl, o-methoxybenzyl, and o-nitrobenzyl can be used. The above optically active epoxy compound ()
The substituent R ₂ of the amino group is a group that leaves in the inversion step, and industrially, R ₂ is preferably a methyl or ethyl group. By treating these optically active epoxy compounds () with water or a basic aqueous solution, they can be converted into inverted N-substituted aminopropanediol. The base used in the present invention includes inorganic bases such as sodium hydroxide, calcium hydroxide, potassium hydroxide, barium hydroxide, aluminum hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, calcium carbonate, and barium carbonate. can. Water is preferred as a solvent, but aromatic hydrocarbons such as benzene and toluene; alcohols such as methanol and ethanol; halogenated hydrocarbons such as methylene chloride and chloroform; ethers such as dioxane ethyl ether and tetrahydrofuran; and dimethyl formamide A mixed system of water and a polar solvent such as dimethyl sulfoxide or acetonitrile 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. When a base is used in this reaction, the normality of the reaction system can be up to about 3 normal. If this reaction is carried out under these reaction conditions, the reaction will last from several hours to
It can be completed within 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. By concentrating the separated organic layer under reduced pressure, an optically active N-substituted aminopropanediol having an inverted steric configuration is obtained. When the target substance is a crystal, it can be easily obtained by filtering the precipitated crystal. If necessary, it can be purified by recrystallization with a solvent such as acetone. Furthermore, if the target product is a liquid, a highly pure product can be obtained as is, but it can also be purified by distillation or a column if necessary. Hereinafter, the present invention will be explained in detail with reference to Examples. Reference example 1 (5R)-3-t-butyl-5-hydroxymethyl-oxazolidin-2-one [a] ²⁰ _D = -44.7°
Dissolve 3.0 g of (C=1, CHCl ₃ ) in 30 ml of 6N-NaOH and stir at 95°C 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-butylamino-1,
2.4 g of white crystals of 2-dihydroxypropane are obtained. [a] ²⁰ _D = +31° (C = 1, 1N HCl) m・p = 84° ~ 85°C 1H NMR (CDCl ₃ , 90MHz) δ ppm 1.15 (9H, S, C (CH ₃ ) ₃ ), 2.45 ~2.80 (2H, _-CH2 -HN-), 2.80-3.20 (3H, HO- _CH2- CH(OH)-
CH ₂ −NH−), 3.45 to 3.75 (3H, HOCH ₂ −
CH(OH)-) Reference example 2 (5R)-3-isopropyl-5-hydroxymethyl-oxazolidin-2-one [a] ²⁰ _D =-
57.6° (C=1, CHCl ₃ ) 4.0g in 6N-NaOH 30ml
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, 3.0 g of liquid (R)-3-isopropylamino-1,2-dihydroxypropane is obtained.
is obtained. [a] ²⁰ _D = +33.9° (C = 1, 1N HCl) b・p = 97°C (1 mmHg) 1H NMR (CDCl ₃ , 90MHz) δ ppm 1.02 to 1.18 (6H, d, CH (CH ₃ ) ₂ ) 2.45 to 2.90 (3H, −CH ₂ NH−) 3.40 to 3.90 (6H, HOCH ₂ CH (OH) CH ₂ NHCH
) Example 1 2.4 g of (R)-3-t-butylamino-1,2-dihydroxypropane obtained in Reference Example 1 was added to 40 ml of hydrogen bromide-acetic acid solution (25%), and
Stir for an hour. After the reaction, the reaction solution is concentrated under reduced pressure to precipitate crystals. The crystals were 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 was added to methanol.
Dissolve in 10 ml, and add 2.5 g of sodium methoxide (28% methanol solution) dropwise to this solution while cooling. Stir for 30 minutes after addition. After the reaction, the reaction solution is concentrated under reduced pressure. Add 20ml 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-t-butylamino-1,2-epoxypropane is obtained. The entire amount was dissolved in 5 ml of methylene chloride, and 5 ml of water was added. A solution of 0.8 g of ethyl chlorocarbonate 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. , stir 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, 1.1 g of liquid (R)-N-ethoxycarbonyl-3-t-butylamino-1,2-epoxypropane is obtained. The obtained (R)-N-ethoxycarbonyl-3
-t-butylamino-1,2-epoxypropane
Add 1.0g to an aqueous solution adjusted to pH 12 with NaOH,
Stir at room temperature for 7 hours. After the reaction, sodium hydroxide is added to the reaction 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, (S)-
0.65 g of white crystals of 3-t-butylamino-1,2-dihydroxypropane are obtained. [a] ²⁰ _D = -31° (C = 1,1N HCl) Example 2 3.0 g of (R)-3-isopropylamino-1,2-dihydroxypropane obtained in Reference Example 2 was added to 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. Stir at room temperature for 5 hours.
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, 3.7 g of potassium carbonate was added and extracted 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.
When methylene chloride is distilled off under reduced pressure, crude (R)-1,2
9.4 g of p-toluenesulfonate of -dihydroxy-3-isopropylaminopropane-1-p-toluenesulfonate are obtained. Next, a portion of 5.8 g of the salt obtained by reconsolidating this salt with isopropyl alcohol was dissolved in 50 ml of methanol, and sodium methoxide (28% methanol solution) was added to this solution.
Add 5.2g dropwise while cooling. Stir for 30 minutes after addition. After the reaction, the reaction solution is concentrated under reduced pressure. Add 50 ml 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, a liquid of (R)-3-isopropylamino-1,2-epoxypropane is obtained. Dissolve the entire amount in 10 ml of methylene chloride, add 10 ml of water, and add 1.8 ml of ethyl chlorocarbonate.
A solution of g dissolved in 10 ml of methylene chloride and a solution of 2.2 g of potassium carbonate dissolved in 10 ml of water were mixed under cooling.
Add dropwise at the same time 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 is distilled off under reduced pressure,
(R)-N-ethoxycarbonyl-3-isopropylamino-1,2-epoxypropane liquid
Obtain 1.8g. The obtained (R)-N-ethoxycarbonyl-3
- Add 1.0 g of isopropylamino-1,2-epoxypropane to an aqueous solution adjusted to pH 12 with NaOH,
Stir at room temperature for 6 hours. After the reaction, sodium hydroxide is added to the reaction solution and extracted with methylene chloride. Dry the methylene chloride layer with anhydrous magnesium sulfate. Distilling methylene chloride under reduced pressure yields 0.65 g of liquid. This product is further purified by distillation to obtain 0.58 g of liquid (S)-3-isopropylamino-1,2-dihydroxypropane. [a] ²⁰ _D = -33.9° (C = 1, 1N HCl) Example 3 (R)-N-ethoxycarbonyl-3-t-butylamino-1, obtained in the same manner as Reference Example 1,
Add 1.0 g of 2-epoxypropane to 10 ml of water and stir at room temperature for 48 hours. After the reaction, sodium hydroxide is added to the reaction solution and extracted with methylene chloride. Dry the methylene chloride layer with anhydrous magnesium sulfate. Crystals are obtained from which methylene chloride is distilled off under reduced pressure. When this is washed with hexane and collected, 0.65 g of white crystals of (S)-3-t-butylamino-1,2-dihydroxypropane is obtained. [a] ²⁰ _D = -31° (C = 1, 1N HCl) Example 4 (R)-N-ethoxycarbonyl-3-t-butylamino-1, obtained in the same manner as in Example 1,
2-Epoxypropane 1.0g to 0.01NK ₂ CO ₃ 20
ml and stir at room temperature for 10 hours. After the reaction, sodium hydroxide is added to the reaction 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, 0.60 g of white crystals of (S)-3-t-butylamino-1,2-dihydroxypropane is obtained. [a] ²⁰ _D = -31° (C = 1, 1N HCl) Example 5 (R)-3-t obtained in the same manner as Example 1
-butylamino-1,2-epoxypropane 1.0
Dissolve g in 5 ml of acetone, add 5 ml of water, and add 0.8 g of ethyl chlorocarbonate to 5 ml of acetone.
Dissolved solution and 1.1 g of potassium carbonate in 5 ml of water.
The dissolved solution is added dropwise at the same time under cooling and stirred for 12 hours at room temperature. After the reaction, acetone is distilled off from the reaction solution under reduced pressure, sodium hydroxide is added, and the mixture is 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 taken, (S)-3-t-butylamino-1,
0.7 g of white crystals of 2-dihydroxypropane are obtained. [a] ²⁰ _D = -31° (C = 1, 1N HCl)

Claims (1)

[Claims] 1 General formula () (In the formula, * indicates an asymmetric carbon. R ¹ is a carbon number of 1
~4 lower alkyl group. ) After reacting the optically active aminopropanediol represented by HBr-acetic acid or deriving it into an optically active tosylate form with p-toluenesulfonyl chloride, it is converted into an epoxy derivative with a base, and then converted with a chlorocarbonate compound. By converting the amino group of the epoxy derivative into a carbamate group, the general formula () (In the formula, * indicates an asymmetric carbon. R ¹ is the same as above, R ² indicates a lower alkyl group having 1 to 4 carbon atoms or a benzyl group.) The general formula () is characterized in that it is then reacted with water or a basic aqueous solution. (In the formula, * and R ¹ are the same as above.) A method of inverting the configuration to an optically active aminopropanediol represented by the following. 2. The method according to claim 1, wherein R ¹ is an isopropyl group or a t-butyl group. 3. The method according to claim 1, wherein R ² is a methyl group or an ethyl group. 4. The method according to claim 1, wherein the solvent during the inversion is water. 5. The method according to claim 1, wherein the base of the basic aqueous solution is an inorganic base. 6. The method according to claim 5, wherein the inorganic base is an alkali hydroxide or an alkali carbonate.