JP2973545B2 - Optically active oxazolidinone derivative and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an optically active β-
The present invention relates to an optically active oxazolidinone derivative such as an optically active 3-benzyl-4-hydroxymethyl-2-oxazolidinone useful as a chiral synthetic synthon in the synthesis of hydroxy-α-amino alcohol and the like, and a method for producing the same.

[0002] Optically active 3-benzyl-4-hydroxymethyl-2-oxazolidinone is considered to be useful as a raw material for synthesizing biologically active substances such as amino acids, amino sugars and sphingolipids having an optically active amino alcohol partial structure. It is expected to be used not only as a chiral auxiliary in asymmetric synthesis but also as an industrially useful substance.

[0003]

2. Description of the Related Art Generally, when producing an optically active compound, it is important that the operation is simple, the yield is good, and the optical purity is kept high. As a production method that meets such a demand, there is a method of synthesizing a chiral intermediate that is easily converted into a chemical, and producing an objective substance through this compound. The important point in this method is that the chiral intermediate is a material which is easy to handle in terms of operation, is inexpensive and can be obtained in large quantities. For example, it is known that optically active amino alcohols can be produced using amino acids as starting materials. Amino acids are relatively inexpensive and useful among chiral materials, but natural amino acids are L
It is a shape. Therefore, when trying to obtain a compound having a structure opposite to the stereochemical structure of a natural compound, the method using an amino acid as a starting material as described above may not be applicable.

In general, the ability to freely produce desired optical isomers is extremely important in producing pharmaceuticals and other organic compounds having biological activity. In view of the above, an object of the present invention is to provide a novel intermediate which is important for producing an optically active amino alcohol and a method for producing the same.

[0005]

The optically active oxazolidinone derivative according to the present invention has the general formula

[0006]

Embedded image

Wherein R is a substituted or unsubstituted aralkyl group, and * is an asymmetric carbon atom.

In the above formula, a typical example of a substituted or unsubstituted aralkyl group represented by R is a benzyl group having no substituent. Therefore, a typical example of the optically active oxazolidinone derivative according to the present invention is optically active 3-benzyl-4-.
Hydroxymethyl-2-oxazolidinone. Examples of the substituted or unsubstituted aralkyl group other than the above-mentioned benzyl group include phenethyl group, α-methylbenzyl group, groups having a lower alkyl group or other substituent on the benzene ring of these aralkyl groups, and benzyl having the same substituent. Is mentioned.

The optically active oxazolidinone derivative according to the present invention can be produced by reacting optically active glycidol with aralkyl isocyanate under basic conditions. In this reaction, the addition of glycidol to the aralkyl isocyanate and the formation of the oxazolidinone ring proceed in one operation.

A typical example of aralkyl isocyanate is unsubstituted benzyl isocyanate. In this case, the production method of the present invention is represented by the following reaction formula.

[0011]

Embedded image

(Wherein Ph represents a phenyl group and * represents an asymmetric carbon atom) Other examples of aralkyl isocyanates include phenethyl isocyanate, α-methylbenzyl isocyanate, and a lower alkyl group on the benzene ring of these isocyanates. Other examples include isocyanates having a substituent and benzyl isocyanates having the same substituent.

As the optically active glycidol, an optically active substance which has been applied by the present applicant as having a very high optical purity can be used (Japanese Patent Application Nos. 1-33067 and 1-330368). reference). When benzyl isocyanate is used as the aralkyl isocyanate, the benzyl isocyanate is preferably used in an amount of 1 to 2 equivalents to glycidol, more preferably 1 to 2 equivalents.
Use 1.2 equivalents. As the base to be used, amines are preferable, and triethylamine is particularly preferable from the viewpoint of simplicity of the reaction. However, the base is not limited to an amine. The amount of the base added may be a catalytic amount based on glycidol, but is preferably 0.1 to 0.5 equivalent in consideration of the reaction time and the like.

As the reaction solvent, an anhydrous aprotic solvent such as chloroform, dichloromethane, dimethylformamide, dimethylsulfoxide and the like are appropriately selected and used. The reaction solvent is not limited to the above as long as it does not participate in the reaction.

Regarding the reaction conditions, the reaction temperature is preferably 20 to 50 ° C., particularly preferably 30 to 45 ° C.
The reaction time is preferably 10 to 20 hours, more preferably 15 to 18 hours.

[0016]

According to the present invention, a novel optically active oxazolidinone derivative is created as described above. By using this as a chiral synthetic synthon, a desired optical isomer such as an optically active β-hydroxy-α-amino alcohol can be obtained. It can be produced simply, with high yield and with high optical purity.

[0017]

EXAMPLES Examples showing synthesis examples of the optically active oxazolidinone derivative according to the present invention and reference examples for confirming the high optical purity thereof will be given below.

[Examples] R-(+)-glycidol was converted to (S)-(+)-3-b
Benzyl-4-hydroxymethyl-2-oxazolidinone
A solution of 556 mg (7.5 mmol) of R-(+)-glycidol having an optical purity of 98% (ee) or more in 5 ml of dichloromethane was dried in 1.9 ml of triethylamine (1.35 mmol).
l) and 1.0 g (7.5 mmol) of benzyl isocyanate
(Aldrich) at room temperature. The resulting mixture was warmed to about 35 ° C. and stirred for 18 hours. After distilling off dichloromethane and triethylamine under reduced pressure, the remaining solid was immediately subjected to column chromatography on silica gel to collect an eluate of diethyl ether / dichloromethane (= 3: 5), and the solvent was distilled off under reduced pressure. This left 1276 mg of (S)-(+)-3-benzyl-4-hydroxymethyl-2-oxazolidinone (82% yield).

The physical properties of this compound are as follows: mp 74-75 ° C. IR (CHCl ₃ ) 3688, 3624, 3452, 1742, 1524, 142
8, 1212 cm ^-1 . NMR (CDCl ₃ ) 2.72 (1H, OH), 3.4-4.8 (7H, m)
, 7.32 (5H, s) [α] _D ²² +29.7 (c = 1.31, CHCl ₃ ) Elemental analysis Measurement values C: 63.70%, H: 6.30%, N: 6.72% As C ₁₁ H ₁₃ O ₃ N ₁ C: 63.75%, H: 6.32%, N: 6.76% [Reference Example] Optical purity of (S)-(+)-3-benzyl-4-hydroxymethyl-2-oxazolidinone obtained in Example The following experiment was performed in order to find out.

A ) (S)-(+)-3-benzyl-4
-Hydroxymethyl-2-oxazolidinone to (S)
-(-)-3-benzyl-4-benzoyloxymethyl
Synthesis of -2-oxazolidinone 0.2 ml of triethylamine was added to a solution of 207 mg (1 mmol) of (S)-(+)-3-benzyl-4-hydroxymethyl-2-oxazolidinone in 3 ml of methylene chloride under cooling.
(1.3 mmol) and 0.13 ml (1.1 mm) of benzoyl chloride
ol) and the resulting mixture was stirred at the same temperature for 1 hour. After adding 1 ml of methanol to the reaction mixture and stirring for 20 minutes, the reaction mixture was poured into ice water and extracted with ether. The obtained organic layer was collected, washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a semi-solid. This was subjected to column chromatography on silica gel, and the effluent from the elution solvent hexane / ethyl acetate (= 2: 1 to 1: 1) was collected, and the solvent was distilled off under reduced pressure to give (S)-(-)- 3-benzyl-4-
Benzoyloxymethyl-2-oxazolidinone 310
mg (quantitative) crystals were obtained.

The physical properties of this compound are as follows: mp 46-47 ° C. IR (CHCl ₃ ) 3688, 3624, 1750, 1604, 1524, 142
6, 1270, 1208, 1118, 1098, 1070, 1030, 928 cm ^-1 . NMR (CDCl ₃ ) 3.9-4.9 (7H, m), 7.25-8.1 (10H, m). [Α] _D ²² -35.1 (c = 0.87, CHCl ₃ ) b) (L) -Nt -butoxycarbonyl -O-ben
(R)-(-)-4-B
Synthesis of nzoyloxymethyl -2-oxazolidinone P. Garner described in J. Org. Chem. , 52, 2361 (1987).
(L) -Nt according to the method of JM Park
To a solution of 500 mg (1.57 mmol) of -butoxycarbonyl-O-benzylserine methyl ester in 8 ml of toluene,
0.42 ml of diisobutylaluminum hydride at -78 ° C
(2.35 mmol) was added dropwise, and the mixture was stirred at -78 ° C for 2 hours. After 1 ml of methanol was slowly added dropwise to the reaction mixture, the reaction mixture was poured into an ice-cooled 1N aqueous hydrochloric acid solution, and extracted with ethyl acetate. The obtained organic layer was collected, washed with brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the corresponding aldehyde generated by reduction of the ester as an oil.

This aldehyde was immediately dissolved without purification in a mixed solvent of 10 ml of isopropanol and 10 ml of tetrahydrofuran, and 190 mg (5 mmol) of sodium borohydride was added little by little under ice-cooling. The reaction mixture was stirred under ice cooling for 30 minutes, diluted with ethyl acetate, and poured into an ice-cooled 1N aqueous hydrochloric acid solution. The mixture was extracted with ethyl acetate, and the organic layer was collected, washed with saturated saline, dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure.
The corresponding alcohol resulting from the reduction of the aldehyde was obtained.

This alcohol was dissolved in 5 ml of dimethylformamide without purification, and 77 mg (1.92 mmol) of 60% oily sodium hydride was added little by little at room temperature to obtain 1
Stirring was performed for hours. After adding an aqueous solution of ammonium chloride to the reaction mixture under ice cooling, extraction was performed with methylene chloride,
The organic layer was collected, washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product of 4-benzyloxymethyl-2-oxazolidinone.

This crude product was dissolved in 15 ml of dry methylene chloride without purification, and ozone was passed through the solution under ice cooling. After confirming the disappearance of the starting material benzyl ether by thin layer chromatography, dimethyl sulfide was added, and the resulting mixture was stirred for 1 hour under ice cooling. The solvent was distilled off under reduced pressure, and the resulting crude crystals were crystallized from a mixed solvent of methylene chloride and hexane to give (R)-(−)-4-
Benzoyloxymethyl-2-oxazolidinone 324
mg (yield 84% in 4 steps).

[Α] _D ²² -28.1 ° (c = 1.03, CHCl ₃ ) c) (R)-(−)-4-benzoyloxymethyl-
From 2-oxazolidinone to (R)-(+)-3-benzyl
4-benzoyloxymethyl-2-oxazolidino
478 mg (2.16 mmol) of (R)-(-)-4-benzoyloxymethyl-2-oxazolidinone obtained in the previous step of the synthesis of
To a solution of the above in 10 ml of tetrahydrofuran was added 121 mg (3.03 mmol) of 60% oily sodium hydride under ice-cooling.
The resulting mixture was stirred for 15 minutes. Then, 555 mg (2.16 mmol) of tetramethylammonium iodide was added, and 0.31 ml (2.59 mmol) of benzyl bromide was further added.
l) and 3.5 ml of dimethylformamide. The reaction mixture was stirred at 0 ° C. for 2.5 hours and then at room temperature for 1.
Stir for 5 hours. The reaction mixture was neutralized by adding citric acid to the reaction mixture under ice cooling, and then extracted with ethyl acetate. The obtained organic layer was collected, washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a semi-solid. This semi-solid was subjected to silica gel column chromatography, and the elution solvent hexane / ethyl acetate (= 2:
The effluent from 1) is collected and the solvent is distilled off under reduced pressure.
580 mg of (R)-(+)-3-benzyl-4-benzoyloxymethyl-2-oxazolidinone was obtained as crystals (yield 86%).

Mp 46-47 ° C. [α] _D ²² -34.4 ° (c = 1.30, CHCl ₃ ) d) Measurement of specific rotation Obtained by O-benzoylation of a 4-hydroxy group by the method described in a) above. (S)-(-)-3-benzyl-4-
Specific rotation [α] _{D of} benzoyloxymethyl-2-oxazolidinone and (R) obtained by the method of b) above.
(R)-(+)-3-Benzyl-4-benzoyloxymethyl-2-oxazolidinone obtained by N-benzylation of-(-)-4-benzoyloxymethyl-2-oxazolidinone according to the above method c). Specific rotation [α]
_{And D} were measured, and the absolute values of the obtained values were compared.

The specific rotation of the former is [α] _D ²² -35.1.
° (C = 0.87, CHCl ₃ ), the specific rotation of the latter is [α] _D ²² + 34.4 ° (C = 1.30, CHCl ₃ )
₃ ), and since these absolute values are close to each other, the optically active 3-benzyl-4-hydroxymethyl-2-oxazolidinone produced by the method of the present invention has a very high optical purity. It was confirmed that there was.

Claims (4)

(57) [Claims] 1. A compound of the general formula (Wherein, R represents a substituted or unsubstituted aralkyl group, and * represents an asymmetric carbon atom, respectively). 2. The optically active oxazolidinone derivative according to claim 1, which is an optically active 3-benzyl-4-hydroxymethyl-2-oxazolidinone. 3. The process for producing an optically active oxazolidinone derivative according to claim 1, wherein the optically active glycidol and the aralkyl isocyanate are reacted under basic conditions. 4. The method for producing an optically active oxazolidinone derivative according to claim 3, wherein the aralkyl isocyanate is benzyl isocyanate.