JPH0692920A - Optically active @(3754/24)r)-2-acylamino-1-arylethanol derivative and its production - Google Patents

Abstract

PURPOSE:To provide a new optically active (R)-2-acylamino-1-arylethanol derivative useful as a starting raw material for pharmaceuticals and physiologically active substances. CONSTITUTION:The (R)-2-acylamino-1-arylethanol derivative of formula I (R<1> is 1-6C aliphatic acyl, acyl having aromatic ring or heterocyclic group or aromatic sulfonyl; R<2> is aryl), e.g. (R)-2-acetamido-1-phenylethanol. The compound of formula I can be produced by treating an alpha-acylaminoacetophenone derivative of formula II with baker's yeast in an inert solvent (especially preferably water or organic solvent). The compound of formula I is useful as an intermediate for optically active (R)-1-amino-1-arylethanol compound of formula III.

Description

Detailed Description of the Invention

[0001]

The present invention relates to an optically active (R) -2
And an acylamino-1-arylethanol derivative, and a method for producing the same. Optical activity (R)-
The 2-acylamino-1-arylethanol derivative is useful as an intermediate for the optically active (R) -1-amino-1-arylethanol compound. This optically active (R) -1-amino-1-arylethanol compound has the following general formula (III):

[Chemical 3] [Wherein R ² represents an aryl group], and is extremely useful as various alkaloids, synthetic intermediates for pharmaceuticals, and physiologically active substances.

[0002]

Various compounds are known as starting compounds for producing the formula (III) (eg, Tetrahedron, 46, 1653 (1990) Synthesis, 575). Page (1990)], a raw material compound for producing a highly pure substance simply and economically is not known.

Therefore, it has been desired to develop a new intermediate compound which enables economical production of (R) -2-amino-1-arylethanol having high optical purity with a simple operation.

[0004]

DISCLOSURE OF THE INVENTION The present invention provides a method for efficiently and economically producing (R) -2-amino-1-arylethanol (formula (III)) having high optical purity by a simple operation. It is intended to provide an intermediate compound and a method for producing the same.

[0005]

Means for Solving the Problems The inventors of the present invention have conducted earnest studies on a simple and highly efficient process for producing a compound of formula (III) and an acyl derivative having extremely high optical purity, and as a result, (R) -2 Finds that -acylamino-1-arylethanol derivatives are very useful as intermediate compounds for the preparation of compounds of formula (III), and that these compounds treat α-acylaminoacetophenone derivatives with baker's yeast The present invention has been completed by finding that it can be manufactured more efficiently.

That is, the (R) -2-acylamino-1-arylethanol derivative of the present invention has the following general formula (I):

[Chemical 4] [In the formula, R ¹ represents an aliphatic acyl group having 1 to 6 carbon atoms, an acyl group having an aromatic ring or a heterocycle, or an aromatic sulfonyl group, and R ² represents an aryl group. ] Is represented.

Further, the method for producing the (R) -2-acylamino-1-arylethanol derivative of the present invention has the following general formula (II):

[Chemical 5] [In the formula, R ¹ represents an aliphatic acyl group having 1 to 6 carbon atoms, an acyl group having an aromatic ring or a heterocycle, or an aromatic sulfonyl group, and R ² represents an aryl group. ] The α-acylaminoacetophenone derivative represented by the above formula is treated with baker's yeast in an inert solvent.

In the method of the present invention, water or an organic solvent is preferably used as the inert solvent.

[0009]

The (R) -2-acylamino-1-arylethanol derivative of the present invention has the chemical structure of formula (I), and the aliphatic acyl group represented by R ¹ in formula (I) is Having 1 to 6 carbon atoms, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl group, preferably acetyl, propionyl, butyryl group, more preferably, It is an acetyl group.

In formula (I), the acyl group having an aromatic ring represented by R ¹ is, for example, a phenyl group or a naphthyl group, preferably a phenyl group. Further, the aromatic ring acyl group may have a substituent on the ring, and as the substituent, an alkyl group having 1 to 4 carbon atoms (for example, a methyl group, an ethyl group, a propyl group, or a butyl group). ), An alkoxy group having 1 to 4 carbon atoms (eg, methoxy, ethoxy, propoxy, and butoxy groups), a halogen atom (eg, fluorine, chlorin, bromine,
And iodo atom), a nitro group, or the like.

In the formula (I), the heterocyclic acyl group represented by R ¹ is, for example, furoyl, tinoyl, nicotinoyl, or isonicotinoyl group,
Preferred are furoyl and tynoyl groups.

In formula (I), examples of the aromatic sulfonyl group represented by R ¹ include an aromatic sulfonyl group having a phenyl group or a naphthyl group. Further, the aromatic ring may have a substituent, and as the substituent, an alkyl group having 1 to 4 carbon atoms (for example, methyl, ethyl, propyl, isopropyl,
Or a butyl group), an alkoxy group having 1 to 4 carbon atoms (eg, methoxy, ethoxy, propoxy, or butoxy group), or a halogen atom (eg, fluorine, chlorin, or bromine atom). A preferred aromatic sulfonyl group is a tosyl group (p-toluenesulfonyl group).

In formula (I), the aryl group represented by R ² is, for example, a phenyl or naphthyl group, and preferably a phenyl group. The aryl group may have a substituent on its ring, and examples of the substituent include an alkyl group having 1 to 4 carbon atoms (for example, a methyl, ethyl, propyl, or butyl group), a carbon number of 1 To 4 alkoxy groups (eg, methoxy, ethoxy, propoxy, or butoxy groups), halogen atoms (eg, fluorine, chlorin, or bromine atoms) and the like.

In the general formula (I), (1) R
¹ represents an aliphatic acyl group having 1 to 6 carbon atoms, an aromatic ring, an acyl group having a heterocycle, or an aromatic sulfonyl group, and (2) R ² represents a phenyl group or a substituent on the ring. It is preferable that the phenyl group has a phenyl group.

Further, the compound of formula (I) preferably has the groups shown in Table 1 as R ¹ and R ² .

[0016]

[Table 1]

The compound of formula (I) of the present invention can be easily produced by the following step (A).

[Chemical 6] [In the above formula, R ¹ and R ² are as defined above]

Step A is the method of the present invention for producing the compound of formula (I), which comprises treating the α-acylaminoacetophenone derivative having the general formula (II) with baker's yeast in an inert solvent. A compound of formula (I) is obtained.

The baker's yeast used in the method of the present invention includes live yeast, dry yeast, and
And immobilized baker's yeast immobilized on a polymer compound such as acrylic amide polymer.

The inert solvent used in the method of the present invention is not limited in kind and composition as long as it does not participate in the reaction, but water or an organic solvent is preferably used. Examples of the organic solvent include ethers such as ether, isopropyl ether, tetrahydrofuran and dioxane, aliphatic hydrocarbons such as pentane, hexane and cyclohexane, aromatic hydrocarbons such as benzene, toluene and xylene, and dichloromethane. Examples thereof include halogenated hydrocarbons such as dichloroethane, chloroform and carbon tetrachloride, and particularly preferred are ethers, aliphatic hydrocarbons and aromatic hydrocarbons.

The reaction temperature in the method of the present invention is usually preferably 0 ° C to 100 ° C, more preferably 20 ° C.
C to 50C. The time required for the reaction varies depending on the type of yeast, the reaction temperature, etc., but is generally 3 hours to 1500 hours (preferably 1 day to 30 days).

The reaction mixture obtained by the process of the invention is
The compound of formula (I) and the unreacted compound of formula (II) are included, but the compound of formula (I) and the compound of formula (II) can be separated and collected from the reaction mixture according to a conventional method. For example, baker's yeast is filtered off from the reaction mixture, the solvent is further distilled off, and then the compound of formula (I) and the compound of formula (II) are separated from the reaction mixture by a conventional method such as column chromatography. Can be collected.

The compound of the formula (I) of the present invention can be easily converted into the compound of the formula (III) having a high optical purity, which is an important intermediate for the synthesis of pharmaceuticals and the like, by the following step (B).

[Chemical 7] [In the above formula, R ¹ and R ² are as defined above]

Step (B) is a step of preparing a 2-amino-1-arylethanol derivative having the general formula (III) from the compound of the formula (I), which comprises reacting the compound of the formula (I) in an inert solvent. This is accomplished by treating the compound with an acid such as dilute hydrochloric acid or dilute sulfuric acid, or an aqueous solution of sodium hydroxide or potassium hydroxide to hydrolyze the compound.

The inert solvent used in the step (B) is not particularly limited as long as it does not participate in the reaction, but is, for example, water, tetrahydrofuran, or ethers such as dioxane, methanol, ethanol, or isopropanol. You can give alcohol,
Preferably alcohols, particularly preferably methanol,
Ethanol and water.

The reaction temperature in step (B) is usually preferably 0 ° C. to 150 ° C., more preferably 20 ° C.
The reaction time is usually from 10 minutes to 24 hours, although it depends on the reaction temperature and the like. After completion of the reaction, the target compound of formula (III) is collected from the reaction mixture according to a conventional method. For example, by distilling off the solvent from the reaction mixture, or by mixing the reaction mixture with water and neutralizing with an alkali when the hydrolyzing agent is an acid, or when the hydrolyzing agent is an alkali, the water is not mixed with water. Extracted from the reaction mixture by extraction with a miscible organic solvent, drying and evaporation of the solvent. Further, if necessary, the compound of formula (III) can be purified by a conventional method, for example, a column chromatography method, a recrystallization method, or the like.

[0027]

The present invention will be described in more detail with reference to the following examples and application examples. Example 1 of (R) -2-acetamido-1-phenylethanol
To an aqueous solution (700 ml) of synthetic Shukurosu (70 g), add 3
Baker's yeast (70 g) was added little by little at 2 ° C. with stirring, and the stirring was continued at the same temperature for 30 minutes. To this solution was added α-acetamidoacetophenone (1 g) in ethanol (20 g).
solution) was gradually added, and baker's yeast (5 g) and water (50 ml) were added and reacted every 2 days while stirring at 32 ° C. After 21 days, acetone (200 ml) was added to stop the reaction, yeast was removed by filtration, the filtrate was concentrated under reduced pressure, extracted with chloroform, dried and purified by recrystallization,
(R) -2-acetamido-1-phenylethanol was obtained as colorless crystals in a yield of 20% (optical purity 26% e
e). Melting point: 134 to 137 ° C. Optical rotation: [α] _D ²⁰ = -22.5 ° (c = 0.75, C
HCl ₃ ) NMR spectrum (DMSO-d ₆ ) δppm: 1.8
2 (3H, s), 3.09 (2H, m), 4.40 (1
H, br-s), 4.61 (1H, d-d), 7.28.
(5H, s), 7.84 (1H, br-s)

Application Example 1 Synthesis of (R) -2-amino-1-phenylethanol A solution of (R) -2-acetamido-1-phenylethanol (0.486 g) obtained in Example 1 in methanol (10
10% hydrochloric acid (5 ml) was added to the mixture (ml) and the mixture was refluxed for 2 hours.
Water (50 ml) was added thereto, neutralized with a 5% sodium carbonate solution, extracted with ether, dried, concentrated, and purified by silica gel column chromatography (eluting solvent: hexane) to give a pale yellow oily product (0.1%). 357 g was obtained (95% yield, 26% optical purity). Melting point: 61 to 63 ° C. Optical rotation: [α] _D ²⁰ = -12.4 ° (c = 0.25, C
HCl ₃ ) NMR spectrum (CDCl ₃ ) δppm: 2.72
(4H, br-s), 4.60 (1H, br-s),
7.34 (5H, m)

Example 2 (R) -2-acetamido-1- (4-chlorophenyi)
1) Synthesis of ethanol α-acetamido-4-chloroacetophenone (1 g)
Was treated in the same manner as in Example 1 to obtain (R) -2-acetamido-1- (4-chlorophenyl) ethanol as colorless crystals in a yield of 70% (optical purity 90
%). Melting point: 135 to 138 ° C. Optical rotation: [α] _D ²⁰ = −53.8 ° (c = 0.10, C
HCl ₃ ) NMR spectrum (CDCl ₃ ) δppm: 1.81
(3H, s), 3.13 (2H, m), 4.62 (1
H, m), 5.50 (1H, br-s), 7.33 (4
H, s), 7.83 (1H, br-H)

Application Example 2 (R) -2-Amino-1- (4-chlorophenyl) ethane
Synthesis of Nole (R) -2-acetamido-1-obtained in Example 2
By treating (4-chlorophenyl) ethanol in the same manner as in Application Example 1, colorless crystals of (R) -2-amino-1- (4-chlorophenyl) ethanol were obtained in a yield of 85% (optical purity: 90%). ). Melting point: 96 to 98 ° C. Optical rotation: [α] _D ²⁰ = −58.6 ° (c = 0.21, C
HCl ₃ ) NMR spectrum (CDCl ₃ ) δppm: 2.65
(2H, br-s), 2.85 (1H, br-s),
4.73 (1H, s), 7.38 (4H, m)

Example 3 (R) -2-acetamido-1- (4-methoxyphenyi)
B) Ethanol synthesis α-acetamido-4-methoxyacetophenone was treated as in Example 1 to give (R) -2-acetamido-
Colorless crystals of 1- (4-methoxyphenyl) ethanol were obtained with a yield of 71% (optical purity 99.4%). Melting point: 88 to 89 ° C. Optical rotation: [α] _D ²⁰ = -72.4 ° (c = 0.45, C
HCl ₃ ) NMR spectrum (CDCl ₃ ) δppm: 2.13
(3H, s), 3.78 (3H, s), 4.15 (2
H, m), 4.48 (1H, br-s), 4.85 (1
H, br-s), 6.78 (1H, br-s), 7.0
8 (2H, d), 7.43 (2H, d)

Application Example 3 (R) -2-Amino-1- (4-methoxyphenyl) e
Synthesis of tanol (R) -2-acetamido-1-obtained in Example 3
(4-Methoxyphenyl) ethanol was treated in the same manner as in Application Example 1 to obtain colorless crystals of (R) -2-amino-1- (methoxyphenyl) ethanol in a yield of 82% (optical purity 99 .4%). Melting point: 101 to 103 ° C. Optical rotation: [α] _D ²⁰ = −39.2 ° (c = 0.58, C
HCl ₃ ) NMR spectrum (CDCl ₃ ) δppm: 3.14
(2H, m), 3.81 (3H, s), 4.89 (1
H, m), 7.03 (2H, d), 7.38 (2H,
d)

Example 4 (R) -1-Phenyl-2- (p-toluene sulphore
Synthesis of ( mid) ethanol α- (p-toluenesulfoamido) acetophenone was treated in the same manner as in Example 1 to give (R) -1-phenyl-2- (p-toluenesulfoamido) ethanol as colorless crystals. Was obtained in a yield of 72% (optical purity 94.3).
%). Melting point: 97 to 99 ° C. Optical rotation: [α] _D ²⁰ = -77.2 ° (c = 0.24, C
HCl ₃ ) NMR spectrum (CDCl ₃ ) δppm: 2.45
(3H, s), 3.20 (2H, m), 3.52 (1
H, br-s), 4.85 (1H, d-d), 7.15.
(1H, br-s), 7.36 (5H, s), 7.80
(4H, d)

Application Example 4 Synthesis of (R) -2-Amino-1-phenylethanol (R) -1-Phenyl-2- (p-toluenesulfoamido) ethanol was added to 15% hydrochloric acid in ethanol and a sealed tube. After hydrolysis for 5 hours, colorless crystals of (R) -2-amino-1-phenylethanol were obtained in a yield of 65% (optical purity 94%). Optical rotation: [α] _D ²⁰ = −42.3 ° (c = 0.45, C
HCl ₃ )

[0035]

INDUSTRIAL APPLICABILITY The optically active (R) -2-acylamino-1-arylethanol derivative of the present invention is useful as a synthetic intermediate for alkaloids, pharmaceuticals and the like and as a physiologically active substance. Useful as an intermediate compound of a 1-arylethanol compound,
This optically active (R) -2-acylamino-1-arylethanol derivative is produced by the method of the present invention in a simple step,
It can be manufactured efficiently.

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Claims (3)

[Claims] 1. The following general formula (I): [In the formula, R ¹ represents an aliphatic acyl group having 1 to 6 carbon atoms, an acyl group having an aromatic ring or a heterocycle, or an aromatic sulfonyl group, and R ² represents an aryl group. ] The (R) -2-acyl amino-1-aryl ethanol derivative represented by these. 2. The following general formula (II): [In the formula, R ¹ represents an aliphatic acyl group having 1 to 6 carbon atoms, an acyl group having an aromatic ring or a heterocycle, or an aromatic sulfonyl group, and R ² represents an aryl group. ] The production of the (R) -2-acylamino-1-arylethanol derivative according to claim 1, characterized in that the α-acylaminoacetophenone derivative represented by the formula [1] is treated with baker's yeast in an inert solvent. Method. 3. The inert solvent is water or an organic solvent,
The manufacturing method according to claim 2.