JP2001151738A - Method for producing phenylethanolamine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing an aminoalcohol useful as an intermediate of a medicinal and an agrochemical compound, industrially having a high safety, simple, in a high yield and economically. SOLUTION: This method for producing phenylethanolamine comprises a first process of reacting an acetalsulfonate derivative with potassium phthalimide and a second process of deblocking the acetalphthalimide derivative obtained in the first process with an acid, and is characterized by reacting the phenylphthalimide derivative obtained in the second process with hydrazine in an organic solvent not compatible with water, dissolving the precipitated phthalazinedione with an alkaline solution and separating.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a phenylethanolamine derivative. The starting materials and final products of the present invention may be optically active forms.
The compound obtained by the present invention is a compound useful as a raw material for medicines, agricultural chemicals and the like.

[0002]

2. Description of the Related Art Conventionally, as a method of producing a phenylethanolamine derivative, a method of reacting an aldehyde or ketone with sodium cyanide or the like and reducing the resulting cyanohydrin compound to produce the derivative (J. Org. Chem. 37, 33).
5), a method of reacting a styrene oxide derivative with ammonia (Synth. Commun. 3, 177 (1)
973)), a method of producing by reacting potassium phthalimide or the like with an ethanediol derivative as a starting material and hydrolyzing the resulting phthalimide derivative (An
gew. Chem. 80, 986 (1968)).

However, in the method via cyanohydrin, when a cyanohydrin compound is obtained, a toxic cyanide compound is used. Therefore, great care must be taken in handling, and there is a problem such as detoxification of a waste liquid. Also,
In the case of obtaining an optically active substance, a technique such as optical resolution is required separately.

In the method of reacting styrene oxide derivative with ammonia, the produced amino alcohol derivative reacts with styrene oxide to produce secondary and tertiary amines as by-products, thereby selectively producing the desired amino alcohol derivative. It is difficult to do. Furthermore, by-product 2
Since the primary and tertiary amines are separated and removed, a complicated operation is required, which makes it difficult to isolate the desired product.

According to this method, a method of suppressing the generation of by-products by reacting a styrene oxide derivative and ammonia with the presence of a specific amount of water is disclosed in Japanese Patent Laid-Open No.
No. 7628, it is necessary to use an autoclave or the like for the reaction, and it is not suitable for mass production.

On the other hand, a method via a phthalimide derivative (Angew. Chem. 80, 986 (1968))
Is effective in selectively obtaining the desired amino alcohol derivative without secondary or tertiary amine by-products. However, due to problems such as the solubility of the phthalimide derivative as an intermediate, hydrolysis by an acid or a base May not progress.
In this case, the use of hydrazine is generally well known, but in this case, a large amount of solvent must be used to separate phthalazinedione, which precipitates in large quantities, and the production efficiency is low. No problem, but not industrially suitable. Further, the obtained amino alcohol derivative generally has problems such as high water solubility and low extraction efficiency with an organic solvent.

[0007]

The amino alcohol derivative is useful as an intermediate for pharmaceuticals and agrochemicals, but its production method has the problems as described above, and is safe, simple, good in yield and economical. It has been desired to develop a new industrial manufacturing method.

[0008]

Means for Solving the Problems The present inventors have made intensive studies to achieve the above object, and as a result, reacted an acetal sulfonate derivative with potassium phthalimide, and obtained a phenylphthalimide derivative which was immiscible with water. It has been found that the desired amino alcohol derivative can be produced in high purity and high yield by reacting with hydrazine in a solvent and dissolving the separated phthalazinedione in an alkaline solution and separating it, and arrived at the present invention.

That is, the present invention provides the following general formula (1)

Embedded image (Wherein R ₁ and R ₂ are the same or different and each represents a hydrogen atom,
A halogen atom, a hydroxyl group, a linear or branched alkyl group having 1 to 4 carbon atoms, a linear or branched alkoxy group having 1 to 4 carbon atoms, an amino group which may be substituted, a nitro group, A fluoromethyl group or R ₁ , R ₂
Together represent a methylenedioxy group. In the method for producing a phenylethanolamine derivative represented by

(A) The following general formula (2)

Embedded image (Wherein, R ₁ and R ₂ have the same meanings as described above, and R ₃ is 3,4,5,6-tetrahydro- [2H] -pyran-2
And R ₄ represents a linear or branched alkyl group having 1 to 4 carbon atoms or a phenyl group which may be substituted. A) reacting the acetal sulfonate derivative represented by the above with potassium phthalimide;

(B) The following general formula (3) obtained in the first step

Embedded image (In the formula, R ₁ , R ₂ , and R ₃ have the same meaning as described above.)
A second step of deprotecting the acetal phthalimide derivative represented by in the presence of an acid,

(C) The following general formula (4) obtained in the second step

Embedded image (Wherein R ₁ and R ₂ have the same meanings as described above) are reacted with hydrazine in an organic solvent immiscible with water, and the precipitated phthalazinedion is dissolved in an alkaline solution. The present invention relates to a method for producing a phenylethanolamine derivative represented by the general formula (1), which is characterized by separating.

[0013]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below in detail.
Specific examples of the acetal sulfonate derivative used as a raw material in the present invention include 2-phenyl-2- (3,4,5,
6-tetrahydro- [2H] -pyran-2-yloxy)
Ethyl methanesulfonate, 2- (2-chlorophenyl) -2- (1-methoxy-1-methylethyloxy)
Ethyl methanesulfonate, 2- (3-chlorophenyl) -2- (3,4,5,6-tetrahydro- [2H]-
Pyran-2-yloxy) ethyl methanesulfonate, 2- (4-chlorophenyl) -2- (3,4,5,
6-tetrahydro- [2H] -pyran-2-yloxy)
Ethyl methanesulfonate, 2- (2-methylphenyl) -2- (1-methoxy-1-methylethyloxy)
Ethyl methanesulfonate, 2- (3-methylphenyl) -2- (3,4,5,6-tetrahydro- [2H]-
Pyran-2-yloxy) ethyl methanesulfonate, 2- (4-methylphenyl) -2- (3,4,5,
6-tetrahydro- [2H] -pyran-2-yloxy)
Ethyl methanesulfonate, 2- (2-hydroxyphenyl) -2- (1-methoxy-1-methylethyloxy) ethyl methanesulfonate, 2- (3-hydroxyphenyl) -2- (3,4,5,6- Tetrahydro-
[2H] -Pyran-2-yloxy) ethyl methanesulfonate, 2- (4-hydroxyphenyl) -2-
(3,4,5,6-tetrahydro- [2H] -pyran-2
-Yloxy) ethyl methanesulfonate, 2- (2
-Methoxyphenyl) -2- (3,4,5,6-tetrahydro- [2H] -pyran-2-yloxy) ethyl methanesulfonate, 2- (3-methoxyphenyl) -2
-(1-methoxy-1-methylethyloxy) ethyl
Methanesulfonate, 2- (4-methoxyphenyl)-
2- (3,4,5,6-tetrahydro- [2H] -pyran-2-yloxy) ethyl methanesulfonate, 2-
(2-trifluoromethylphenyl) -21-methoxy-1-methylethyloxy) ethyl methanesulfonate, 2- (3-trifluoromethylphenyl) -2-
(3,4,5,6-tetrahydro- [2H] -pyran-2
-Yloxy) ethyl methanesulfonate, 2- (4
-Trifluoromethylphenyl) -2- (3,4,5
6-tetrahydro- [2H] -pyran-2-yloxy)
Ethyl methanesulfonate, 2- (2-aminophenyl) -2- (3,4,5,6-tetrahydro- [2H]-
Pyran-2-yloxy) ethyl methanesulfonate, 2- (3-aminophenyl) -2- (3,4,5,
6-tetrahydro- [2H] -pyran-2-yloxy)
Ethyl methanesulfonate, 2- (4-aminophenyl) -2- (1-methoxy-1-methylethyloxy)
Ethyl methanesulfonate, 2- (2-nitrophenyl) -2- (3,4,5,6-tetrahydro- [2H]-
Pyran-2-yloxy) ethyl methanesulfonate, 2- (3-nitrophenyl) -2- (3,4,5,
6-tetrahydro- [2H] -pyran-2-yloxy)
Ethyl methanesulfonate, 2- (4-nitrophenyl) -2- (3,4,5,6-tetrahydro- [2H]-
Pyran-2-yloxy) ethyl methanesulfonate, 2- (2,4-dichlorophenyl) -2- (3,
4,5,6-tetrahydro- [2H] -pyran-2-yloxy) ethyl methanesulfonate, 2- (2,4-
Difluorophenyl) -2- (3,4,5,6-tetrahydro- [2H] -pyran-2-yloxy) ethyl methanesulfonate, 2- (3,4, -methylenedioxyphenyl) -2- (3, 4,5,6-tetrahydro-
[2H] -Pyran-2-yloxy) ethyl methanesulfonate, 2-phenyl-2- (1-methoxy-1-methylethyloxy) ethyl p-toluenesulfonate, 2- (2-chlorophenyl) -2- (3, 4,5,
6-tetrahydro- [2H] -pyran-2-yloxy)
Ethyl p-toluenesulfonate, 2- (3-chlorophenyl) -2- (3,4,5,6-tetrahydro-
[2H] -Pyran-2-yloxy) ethyl p-toluenesulfonate, 2- (4-chlorophenyl) -2-
(1-methoxy-1-methylethyloxy) ethyl p
-Toluenesulfonate, 2- (2-methylphenyl)
-2- (3,4,5,6-tetrahydro- [2H] -pyran-2-yloxy) ethyl p-toluenesulfonate, 2- (3-methylphenyl) -2- (3,4,5,
6-tetrahydro- [2H] -pyran-2-yloxy)
Ethyl p-toluenesulfonate, 2- (4-methylphenyl) -2- (3,4,5,6-tetrahydro- [2
H] -Pyran-2-yloxy) ethyl p-toluenesulfonate, 2- (2-hydroxyphenyl) -2-
(1-methoxy-1-methylethyloxy) ethyl p
-Toluenesulfonate, 2- (3-hydroxyphenyl) -2- (3,4,5,6-tetrahydro- [2H]-
Pyran-2-yloxy) ethyl p-toluenesulfonate, 2- (4-hydroxyphenyl) -2- (3,
4,5,6-tetrahydro- [2H] -pyran-2-yloxy) ethyl p-toluenesulfonate, 2- (2
-Methoxyphenyl) -2- (3,4,5,6-tetrahydro- [2H] -pyran-2-yloxy) ethyl p
-Toluenesulfonate, 2- (3-methoxyphenyl) -2- (1-methoxy-1-methylethyloxy)
Ethyl p-toluenesulfonate, 2- (4-methoxyphenyl) -2- (3,4,5,6-tetrahydro-
[2H] -pyran-2-yloxy) ethyl p-toluenesulfonate, 2- (2-trifluoromethylphenyl) -2- (3,4,5,6-tetrahydro- [2H]-
Pyran-2-yloxy) ethyl p-toluenesulfonate, 2- (3-trifluoromethylphenyl) -2
-(1-methoxy-1-methylethyloxy) ethyl
p-toluenesulfonate, 2- (4-trifluoromethylphenyl) -2- (3,4,5,6-tetrahydro- [2H] -pyran-2-yloxy) ethyl p-toluenesulfonate, 2- (2- Aminophenyl) -2-
(3,4,5,6-tetrahydro- [2H] -pyran-2
-Yloxy) ethyl p-toluenesulfonate, 2
-(3-aminophenyl) -2- (1-methoxy-1-
Methylethyloxy) ethyl p-toluenesulfonate, 2- (4-aminophenyl) -2- (3,4,5,
6-tetrahydro- [2H] -pyran-2-yloxy)
Ethyl p-toluenesulfonate, 2- (2-nitrophenyl) -2- (3,4,5,6-tetrahydro-
[2H] -Pyran-2-yloxy) ethyl p-toluenesulfonate, 2- (3-nitrophenyl) -2-
(3,4,5,6-tetrahydro- [2H] -pyran-2
-Yloxy) ethyl p-toluenesulfonate, 2
-(4-nitrophenyl) -2- (3,4,5,6-tetrahydro- [2H] -pyran-2-yloxy) ethyl p-toluenesulfonate, 2- (2,4-dichlorophenyl) -2- ( 3,4,5,6-tetrahydro-
[2H] -pyran-2-yloxy) ethyl p-toluenesulfonate, 2- (2,4-difluorophenyl)
-2- (3,4,5,6-tetrahydro- [2H] -pyran-2-yloxy) ethyl p-toluenesulfonate, 2- (3,4-methylenedioxyphenyl) -2-
(3,4,5,6-tetrahydro- [2H] -pyran-2
-Yloxy) ethyl p-toluenesulfonate; Further, each of the acetal sulfonate derivatives mentioned above may be an optically active substance.

The acetal sulfonate derivative defined above can be easily converted to the corresponding acetal phthalimide derivative represented by the above general formula (3) by reacting it with potassium phthalimide in the first step. .

As the reaction solvent in the first step, an organic solvent inert to the reaction can be used alone or in a mixture. For example, aprotic polar solvents such as dimethylformamide, diethylformamide, and dimethylsulfoxide, toluene, Aromatic hydrocarbons such as xylene, halogenated hydrocarbons such as methylene chloride and chloroform, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane and t-butyl methyl ether; ethyl acetate and methyl acetate; Examples thereof include ester solvents and nitrile solvents such as acetonitrile.

[0016] The reaction temperature of the first step can be carried out in the range of 0 to 200 ° C, preferably 20 ° C to 150 ° C. The reaction time varies depending on the reaction solvent and reaction temperature used, but is usually applied within 12 hours, in the range of 0.5 to 8 hours.

In the second step, the acetal phthalimide derivative obtained in the first step can be easily converted to the corresponding phenylphthalimide derivative represented by the above general formula (4) by deprotection in the presence of an acid. it can.

As the acid used in the second step, sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, acetic acid, p-toluenesulfonic acid, methanesulfonic acid and the like can be used. The amount of the acid to be used is 0.1 to the acetal phthalimide derivative.
It can be used in the range of 01 to 3 equivalents, preferably 0.1 to 2 equivalents.

As the reaction solvent in the second step, a solvent inert to the reaction can be used alone or as a mixture. For example, alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol and t-butyl alcohol, toluene , Aromatic hydrocarbons such as xylene, halogenated hydrocarbons such as methylene chloride and chloroform, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane, t-butyl methyl ether, ethyl acetate, methyl acetate and the like Ester solvents, nitrile solvents such as acetonitrile,
Water.

The reaction temperature in the second step can be carried out in the range of 0 to 100 ° C., preferably 20 to 80 ° C. The reaction time varies depending on the acid used, the reaction solvent and the reaction temperature, but is usually applied within 12 hours, in the range of 0.5 to 6 hours.

In the third step, the phenylphthalimide derivative obtained in the second step is reacted with hydrazine in an organic solvent immiscible with water, and the precipitated phthalazinedione is dissolved in an alkaline solution and separated, whereby the phthalazinedione derivative is easily separated. A phenylethanolamine derivative represented by the general formula (1) corresponding to

As the reaction solvent in the third step, a solvent inert to the reaction immiscible with water can be used alone or in a mixture. Examples thereof include aromatic hydrocarbons such as toluene and xylene, methylene chloride, chloroform and the like. And ethers such as diethyl ether, diisopropyl ether and t-butyl methyl ether, and ester solvents such as ethyl acetate and methyl acetate.

The reaction temperature in the third step can be carried out in the range of 0 to 100 ° C., preferably 20 to 80 ° C. The reaction time varies depending on the reaction solvent and the reaction temperature, but is usually applied within 12 hours and in the range of 0.5 to 6 hours.

As the base used in the third step, for example,
Sodium hydroxide, potassium hydroxide and the like can be used.

The concentration of the aqueous alkali solution is 5 to 50.
%, Preferably 10 to 40%.

The temperature at the time of separating the aqueous alkali solution is 2
It can be carried out in the range of 0 to 100 ° C, and preferably 30 to 60 ° C in consideration of operability and the like. Processing time is
It is 0.5 to 3 hours, preferably 0.5 to 1 hour.

The desired amino alcohol derivative can be easily purified after completion of the reaction using a column or the like, if necessary.

When the reaction was carried out using the optically active acetate sulfonate derivative as the starting compound in the above-mentioned manner, the amino alcohol derivatives obtained had the corresponding steric configurations, and were found to be sterically retained. . Thus, it has become possible to provide a corresponding optically active amino alcohol derivative from an optically active acetate sulfonate derivative while maintaining its steric shape.
The optical purity of the obtained optically active amino alcohol derivative was measured by high performance liquid chromatography using an optical resolution column.

[0029]

Next, the present invention will be described more specifically with reference to examples and comparative examples, but the present invention is not limited to these examples.

Comparative Example Preparation of (R) -2-amino-1- (3-chlorophenyl) ethanol 1) (R) -N- [2- (3-chlorophenyl) -2-
(3,4,5,6-tetrahydro- [2H] -pyran-2
Preparation of [-yloxy) ethyl] phthalimide (R) -2- (3-chlorophenyl) -2- (3,4,5,6-tetrahydro-) in dimethylformamide (50 ml)
[2H] -pyran-2-yloxy) ethyl methanesulfonate (10 g) and potassium phthalimide (5.5
5 g) and stirred at 100 ° C. for 6 hours. After cooling the reaction mixture, the precipitated solid was separated by filtration, the filtrate was concentrated, and ethyl acetate and water were added to the obtained residue, followed by extraction with stirring. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the organic layer was concentrated to give the title compound as pale yellow crystals (11.0 g, 95.0%). Was. 2) (R) -2-N- [2- (3-chlorophenyl)-
Preparation of 2-hydroxyethyl] phthalimide (R) -N- [2- (3-
Chlorophenyl) -2- (3,4,5,6-tetrahydro- [2H] -pyran-2-yloxy) ethyl] phthalimide (10 g) was added, followed by 3N hydrochloric acid (9.5 m).
l) was added and the mixture was stirred at 50 ° C for 1 hour. The reaction mixture was cooled, and the precipitated crystals were filtered and dried in vacuo to give the title compound (7.34 g, 94.0%) as white crystals. 3) (R) -2-amino-1- (3-chlorophenyl)
Production of ethanol ((R) -2-N- [2
-(3-Chlorophenyl) -2-hydroxyethyl] phthalimide (5 g) was added, then saturated hydrazine (2.5 g) was added, and the mixture was stirred at 70 ° C for 1 hour. Water (50 ml) was added to the reaction mixture, and the precipitated crystals were filtered. After that, the filtrate was concentrated and extracted with chloroform (25 ml) five times. The combined organic layers were dried over sodium sulfate to give the title compound as white crystals (2.32 g, 82.0%). The overall yield of 1) to 3) was 73.2%. Its optical purity was 99.9% e. e. That was all.

Example 1 (R) -2-amino-1- (3
Production of -chlorophenyl) ethanol 1) (R) -N- [2- (3-chlorophenyl) -2-
(3,4,5,6-tetrahydro- [2H] -pyran-2
Preparation of -yloxy) ethyl] phthalimide (R) -2 in dimethylformamide (100 ml)
-(3-Chlorophenyl) -2- (3,4,5,6-tetrahydro- [2H] -pyran-2-yloxy) ethyl methanesulfonate (20 g) and potassium phthalimide (11.1 g) were added, and the mixture was added at 100 ° C. For 6 hours. After cooling the reaction mixture, the precipitated solid was separated by filtration, the filtrate was concentrated, and ethyl acetate and water were added to the obtained residue, followed by extraction with stirring. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the organic layer was concentrated to give the title compound as pale yellow crystals (21.0 g, 96.
1%). 2) (R) -2-N- [2- (3-chlorophenyl)-
Preparation of 2-hydroxyethyl] phthalimide (R) -N- [2- (3-
Chlorophenyl) -2- (3,4,5,6-tetrahydro- [2H] -pyran-2-yloxy) ethyl] phthalimide (20 g) was added, followed by 3N hydrochloric acid (19 ml).
Was added and stirred at 50 ° C. for 1 hour. The reaction mixture was cooled, and the precipitated crystals were filtered and dried in vacuo to give the title compound as white crystals (14.5 g, 94.2%). 3) (R) -2-amino-1- (3-chlorophenyl)
Production of ethanol (R)-in toluene (150 ml)
2-N- [2- (3-chlorophenyl) -2-hydroxyethyl] phthalimide (10 g) was added, and then saturated hydrazine (5 g) was added, followed by stirring at 70 ° C. for 1 hour. 10% aqueous sodium hydroxide solution (20 g) in the reaction mixture
Was added at the same temperature, and the mixture was stirred for 10 minutes and then separated while maintaining the temperature at 50 ° C. The organic layer was concentrated, and the title compound (5.
5g, 90.3%). The overall yield of 1) to 3) was 81.7%. Its optical purity was 99.9% e. e. That was all.

Example 2 Preparation of (R) -2-amino-1-phenylethanol 1) R) -N- [2-phenyl-2- (3,4,5,6)
Preparation of -tetrahydro- [2H] -pyran-2-yloxy) ethyl] phthalimide (R) -2 in dimethylformamide (100 ml)
-Phenyl-2- (3,4,5,6-tetrahydro-
[2H] -pyran-2-yloxy) ethyl methanesulfonate (20 g) and potassium phthalimide (12.
4 g) and stirred at 100 ° C. for 6 hours. After cooling the reaction mixture, the precipitated solid was separated by filtration, the filtrate was concentrated, and ethyl acetate and water were added to the obtained residue, followed by extraction. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the organic layer was concentrated to give the title compound as pale yellow crystals (21.4 g, 97.0%). Was. 2) Preparation of (R) -2-N-(-phenyl-2-hydroxyethyl) phthalimide (R) -N- [2-phenyl-2- (3,4,5,6-) in methanol (50 ml). Tetrahydro- [2H] -pyran-2-yloxy) ethyl] phthalimide (20
g), and then 3N hydrochloric acid (21 ml) was added.
Stirred at C for 1 hour. The reaction mixture was cooled, and the precipitated crystals were filtered and dried in vacuo to give the title compound (1) as white crystals.
(3.8 g, 92.5%). 3) Preparation of (R) -2-amino-1-phenylethanol (R) -2-N-(-phenyl-2-hydroxyethyl) phthalimide (12 g) in toluene (150 ml)
, Then saturated hydrazine (6 g) was added,
Stir for 1 hour. A 10% aqueous sodium hydroxide solution (22 g) was added to the reaction mixture at the same temperature, and the mixture was stirred for 10 minutes, and then separated while keeping the temperature at 50 ° C. The organic layer was concentrated to give the title compound as white crystals (6.2 g, 93.2%). 1) ~
The overall yield of 3) was 83.6%. Its optical purity was 99.9% e. e. That was all.

Example 3 (S) -2-amino-1- (3
Production of -chlorophenyl) ethanol 1) (S) -N- [2- (3-chlorophenyl) -2-
Preparation of (1-methoxy-1-methylethyloxy) ethyl] phthalimide (S)-in dimethyl sulfoxide (100 ml)
2- (3-chlorophenyl) -1- (methoxy-1-methylethyloxy) ethyl methanesulfonate (20
g) and potassium phthalimide (11.7 g)
Stirred at 100 ° C. for 6 hours. After cooling the reaction mixture, the precipitated solid was separated by filtration, the filtrate was concentrated, and ethyl acetate and water were added to the obtained residue, followed by extraction. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered to remove the desiccant, and concentrated to give the title compound as pale yellow crystals (20.2 g, 92.2%). Was. 2) (S) -N- [2- (3-chlorophenyl) -2-
Preparation of [hydroxyethyl] phthalimide ((S) -N- [2- (3
-Chlorophenyl) -2- (1-methoxy-1-methylethyloxy) ethyl] phthalimide (20 g), followed by p-toluenesulfonic acid monohydrate (11.0
g) was added and the mixture was stirred at 50 ° C. for 1 hour. The reaction mixture was cooled, and the precipitated crystals were filtered and dried in vacuo to give the title compound (14.8 g, 92.9%) as white crystals. 3) (S) -2-amino-1- (3-chlorophenyl)
Production of ethanol (S) -N- [2- (3- (3-
[Chlorophenyl) -2-hydroxyethyl] phthalimide (10 g) was added, and then saturated hydrazine (5 g) was added, followed by stirring at 70 ° C. for 1 hour. A 10% aqueous sodium hydroxide solution (20 g) was added to the reaction mixture at the same temperature.
After stirring for minutes, liquid separation was performed while maintaining the temperature at 50 ° C. The organic layer was concentrated to give the title compound as white crystals (5.5 g, 90.3%). The overall yield of 1) to 3) was 77.3%.
Its optical purity was 99.9% e. e. That was all.

Example 4 (R) -2-amino-1- (4
Production of -chlorophenyl) ethanol 1) (R) -N- [2- (4-chlorophenyl) -2-
(3,4,5,6-tetrahydro- [2H] -pyran-2
Preparation of (R) -2- (4-chlorophenyl) -2- (3,4,5,6-tetrahydro- [2H] -pyran-2-yloxy in dimethylformamide (100 ml) ) Ethyl p-toluenesulfonate (22.0 g) and potassium phthalimide (10.0 g) were added, and the mixture was stirred at 100 ° C for 6 hours. After cooling the reaction mixture, the precipitated solid was separated by filtration, the filtrate was concentrated, and ethyl acetate and water were added to the obtained residue, followed by extraction. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the organic layer was concentrated to give the title compound as pale yellow crystals (18.2 g, 92.9).
%). 2) (R) -N- [2- (4-chlorophenyl) -2-
Preparation of hydroxyethyl] phthalimide (R) -N- [2- (4
-Chlorophenyl) -2- (3,4,5,6-tetrahydro- [2H] -pyran-2-yloxy) ethyl] phthalimide (18 g) and 3N hydrochloric acid (17 m
l) was added and the mixture was stirred at 50 ° C for 1 hour. The reaction mixture was cooled, and the precipitated crystals were filtered and dried in vacuo to give the title compound (12.8 g, 92.3%) as white crystals. 3) (R) -2-amino-1- (4-chlorophenyl)
Production of Ethanol In toluene (150 ml), (R) -N- [2- (4
-Chlorophenyl) -2-hydroxyethyl] phthalimide (10 g), followed by saturated hydrazine (5 g)
Was added and stirred at 70 ° C. for 1 hour. 10% in the reaction mixture
An aqueous sodium hydroxide solution (20 g) was added at the same temperature, and 1
After stirring for 0 minutes, liquid separation was performed while maintaining the temperature at 50 ° C. The organic layer was concentrated to give the title compound as white crystals (5.6 g, 91.9%).
I got The overall yield of 1) to 3) was 78.8%. Its optical purity was 99.9% e. e. That was all.

Example 5 (R) -2-amino-1- (2
Production of -chlorophenyl) ethanol As a raw material, (R) -2- (2-chlorophenyl) -2-
(3,4,5,6-tetrahydro- [2H] -pyran-2
The same procedures as in Example 1 were carried out except using -yloxy) ethyl methanesulfonate, to give the title compound as white crystals in an overall yield of 81.0%. Its optical purity is 99.
9% e. e. That was all.

Example 6 (R, S) -2-amino-1-
Preparation of phenylethanol 1) Preparation of (R, S) -N- [2-phenyl-2- (1-methoxy-1-methylethyloxy) ethyl] phthalimide In dimethylformamide (100 ml), (R, S)
-2-phenyl-2- (1-methoxy-1-methylethyloxy) ethyl methanesulfonate (20 g);
Add potassium phthalimide (15.5 g) and add
For 6 hours. After cooling the reaction mixture, the precipitated solid was separated by filtration, the filtrate was concentrated, and ethyl acetate and water were added to the obtained residue, followed by extraction. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the organic layer was concentrated to give the title compound as pale yellow crystals (22.
8g, 96.7%). 2) Preparation of (R, S) -2-N-(-phenyl-2-hydroxyethyl) phthalimide (R, S) -N- [2-phenyl-2- (1-methoxy-) in methanol (50 ml). 1-methylethyloxy) ethyl] phthalimide (20 g)
N hydrochloric acid (21 ml) was added, and the mixture was stirred at 50 ° C. for 1 hour.
The reaction mixture was cooled, and the precipitated crystals were filtered and dried in vacuo to give the title compound as white crystals (14.5 g, 92.0 g).
%). 3) Preparation of (R, S) -2-amino-1-phenylethanol (R, S) -2-N-(-) in toluene (150 ml)
Phenyl-2-hydroxyethyl) phthalimide (12
g) was added, and then saturated hydrazine (6.8 g) was added, followed by stirring at 70 ° C. for 1 hour. A 10% aqueous sodium hydroxide solution (22 g) was added to the reaction mixture at the same temperature, and the mixture was stirred for 10 minutes, and then separated while keeping the temperature at 50 ° C. The organic layer was concentrated and the title compound as white crystals (5.78 g, 94.0%).
I got The overall yield of 1) to 3) was 83.6%.

[0037]

According to the present invention, a phenylphthalimide derivative obtained using an acetal sulfonate derivative as a starting material is reacted with hydrazine in an organic solvent immiscible with water, and the precipitated phthalazinedion is dissolved in an alkaline solution to be separated. By doing so, the desired ethanolamine derivative can be obtained in high yield and high purity without secondary or tertiary amine by-products. Further, the method of the present invention is suitable as a simple and economical industrial production method with high safety.

Claims (3)

[Claims] [Claim 1] The following general formula (1)(Where R₁, R₂Are the same or different and are a hydrogen atom,
Halogen atom, hydroxyl group, linear or straight-chain having 1 to 4 carbon atoms
Is a branched alkyl group, linear or straight-chain having 1 to 4 carbon atoms
Is a branched alkoxy group, an optionally substituted amino
Group, nitro group, trifluoromethyl group or R₁, R₂
Together represent a methylenedioxy group. )
In the production of phenylethanolamine derivatives
(A) the following general formula (2):(Where R₁, R₂Is the same as above, R₃Are 3, 4, 5,
A 6-tetrahydro- [2H] -pyran-2-yl group or
Represents a 1-methoxy-1-methylethyl group; ₄Is charcoal
A linear or branched alkyl group having a prime number of 1 to 4, or
Represents a phenyl group which may be substituted. )
Acetal sulfonate derivative with potassium phthalimide
(B) the following general formula (3) obtained in the first step:(Where R₁, R₂, R₃Is the same as above. )
Deprotection of acetal phthalimide derivatives in the presence of acid
A second step, (c) the following general formula (4) obtained in the second step:(Where R₁, R₂Has the same meaning as described above. )
Organics that do not mix water with phenylphthalimide derivatives
Phthalazine di, which reacts with hydrazine in a solvent and precipitates
Dissolve and dissolve ON in alkaline solution
The phenylethanol alcohol represented by the general formula (1)
A method for producing a min derivative. 2. The compound represented by the general formula (1) is represented by R
The method for producing a phenylethanolamine derivative according to claim 1, which is in the form of a derivative. 3. The compound represented by the general formula (1) is S
The method for producing a phenylethanolamine derivative according to claim 1, which is in the form of a derivative.