JP2002088031A - Method for producing (s)-1-phenylpropylamine - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for readily producing high-quality (S)-1- phenylpropylamine in high yield from (R)-1-phenylpropyl alcohol. SOLUTION: (R)-1-Phenylpropyl alcohol represented by the following formula (1) is reacted with diphenylphosphoryl azide as an azidation agent in the presence of a base to provide (S)-1-phenylpropyl azide represented by the following formula (2), which is then subjected to hydrogenating reaction in the presence of palladium carbon to produce the (S)-1-phenylpropylamine represented by the following formula (3).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing (S) -1-phenylpropylamine. (S) -1-phenylpropylamine produced by the present invention is a substance useful as a raw material for synthesis of circulatory drugs and general industrial chemicals.

[0002]

2. Description of the Related Art Conventionally, as a method for producing (S) -1-phenylpropylamine, a crystal of an optically active substance is added as a seed to a saturated solution of racemic 1-phenylpropylamine, and one of the crystals is preferentially crystallized. A dividing method is known (Synthesis (1988) (5) 410).
-11, J.I. Chem. Soc. Perkin Tra
ns. 1, (1989) 7, 1548-1549). However, the isolation operation is complicated, the production cost is increased, and it cannot be said that the method is industrially advantageous.

On the other hand, as an example using a diastereomer method which is a commonly used optical resolution method, a method in which (-)-bantoyl lactone is allowed to act as an optical resolution agent (Japanese Patent Application Laid-Open No. No. 54342). Alternatively, 1-phenylpropylamine is reacted with (S) -α-isopropyl-p-fluorophenylacetic acid as an optical resolving agent in a solvent to form (S) -1-phenylpropylamine and (S) -α-. A method of obtaining a diastereomer salt mixture of isopropyl-p-fluorophenylacetic acid, isolating the diastereomer salt mixture, and treating the isolated diastereomer salt with an alkali (WO00 / 02843) is disclosed. I have. However, these methods use expensive optical resolving agents, require complicated steps, and are not necessarily industrially advantageous because the yield and optical purity are not necessarily high.

[0004]

SUMMARY OF THE INVENTION An object of the present invention is to solve the above-mentioned problems of the prior art and to provide a method for easily producing a high-quality (S) -1-phenylpropylamine in high yield. To provide.

[0005]

Means for Solving the Problems In order to solve the above-mentioned problems, the present inventors have conducted intensive studies, and as a result, using (R) -1-phenylpropyl alcohol as a starting material, an intermediate (S) Considering that the efficient production of 1-phenylpropyl azide is the most important point in the synthesis, the use of diphenylphosphoryl azide as an azidating agent in the azidation of the hydroxyl group of (R) -1-phenylpropyl alcohol makes it possible to stabilize it. A method for synthesizing (S) -1-phenylpropyl azide in one step quantitatively and maintaining optical purity was found. Further, they have found that secondary and tertiary amines are particularly useful as the base used for the azidation. Then, it was found that hydrogenation of (S) -1-phenylpropyl azide in the presence of palladium carbon easily produced the desired (S) -1-phenylpropylamine, and completed the present invention. Was.

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

Embedded image (R) -1-phenylpropyl alcohol represented by (1) is reacted with an azidating agent in the presence of a base to give the following formula (2)

Embedded image (2) After producing (S) -1-phenylpropyl azide represented by the following formula, a hydrogenation reaction is carried out in the presence of palladium carbon, and the following formula (3):

Embedded image This is a production method for obtaining (S) -1-phenylpropylamine represented by (3) in high yield and high optical purity.

[0007]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below in detail.

The starting material (R) -1-phenylpropyl alcohol used in the production method of the present invention may be one produced by a usual production method or a commercially available one.

The azidating agent used in the production method of the present invention can be any one which is usually used, but is preferably diphenylphosphoryl azide. As the diphenylphosphoryl azide, those produced by a usual production method may be used, or those commercially available may be used. The amount of diphenylphosphoryl azide to be used is generally in the range of 1.0 to 1.5 mol, preferably 1.0 to 1.1 mol, per 1 mol of (R) -1-phenylpropyl alcohol. In the azidation reaction, a reaction solvent is not particularly used, but is not limited.

The base used for the azidation reaction in the production method of the present invention is preferably a secondary amine or a tertiary amine, but is not limited thereto. Preferably, secondary amines such as di-n-butylamine and diethylamine, and tertiary amines such as triethylamine, tri-n-butylamine and diazabicycloundecene are used.
The amount of the base used is in the range of 1.0 to 2.0 mol, preferably 1.0 to 1.5 mol, per 1 mol of (R) -1-phenylpropyl alcohol.

The reaction temperature of the azidation reaction is generally required to be in the range of 0 to 30 ° C., since the reaction is difficult to proceed at a low temperature and the reactivity becomes high at a high temperature, but the stereoselectivity is deteriorated. is there. The reaction time after the addition of the base is usually 2 to 24.
The reaction time varies depending on the base added dropwise.
In the case of diazabicycloundecene, it is about 2 hours,
24 for di-n-butylamine and triethylamine
About an hour.

The isolation of (S) -1-phenylpropyl azide from the reaction system is performed by adding a non-water-miscible inert solvent as an extraction solvent, washing the organic layer with water, and concentrating the extraction solvent. After removal, it is obtained by distillation.

Examples of the non-water-miscible inert solvent include, but are not limited to, hexane, heptane, benzene, toluene, and isopropyl ether. The amount of these solvents used is (R)-
1 weight of 1-phenylpropyl alcohol is usually 2
-5 (volume / weight) ratio. The amount of water used for washing is usually in the range of 1 to 5 (volume / weight) relative to 1 weight of (R) -1-phenylpropyl alcohol.

In the hydrogenation reaction of (S) -1-phenylpropyl azide, the amount of 5% palladium carbon used is 0.01 to 0.05 (1% by weight of (S) -1-phenylpropyl azide). (Weight / weight) ratio (in terms of solid content), preferably 0.05 (weight / weight) ratio. The reaction solvent used is an alcohol such as methanol or ethanol or an ester such as ethyl acetate, but is not limited thereto. The amount of the reaction solvent used is in the range of 5 to 10 (volume / weight) ratio, preferably 5 (volume / weight) ratio, based on 1 weight of (S) -1-phenylpropyl azide. The hydrogenation reaction is performed in an open system because nitrogen gas is produced as a by-product, and the hydrogen gas is blown from the liquid using a blowing pipe or the like. At this time, pay attention to the blowing amount so that hydrogen is not extracted. The amount of hydrogen gas blown is
(S) -1-phenylpropyl azide per 1 mol,
1.1 to 1.5 moles, preferably 1.1 to 1.2
Is a mole. The reaction temperature is in the range of 0 to 30 [deg.] C. because a high temperature easily produces by-products. After the reaction, palladium carbon is removed by filtration, and the filtrate is concentrated and distilled to obtain high-purity (S) -1-phenylpropylamine.

[0015]

The following examples illustrate the method of the present invention. However, this is not a limitation of the present invention.

Example 1 Synthesis of (S) -1-phenylpropyl azide 100.0 g of (R) -1-phenylpropyl alcohol in a 1,000 ml four-necked flask equipped with a mechanical overhead stirrer, thermometer, Dimroth condenser
(0.73 mol), diphenylphosphoryl azide 22
2.1 g (0.81 mol) was added, and the mixture was stirred so as to be uniformly mixed. 141.5 g of di-n-butylamine (1.
10 mol) was dropped at 30 ° C. or lower over 3 hours, and the mixture was aged at 10 to 25 ° C. for 24 hours. Heptane 2
70 ml was added, the by-product solid was collected by filtration, and the filtrate was washed with 100 ml of heptane. The filtrate was transferred to a separating funnel, 100 ml of water was added, the organic layer was washed with water, and the aqueous layer was separated. Further, 100 ml of water was added, and the organic layer was washed with water. The organic layer after the washing was subjected to concentration removal of heptane as an extraction solvent using an evaporator, followed by distillation under reduced pressure (under about 5 mmHg,
(Distillation temperature: about 72 ° C.) to obtain 105 g of (S) -1-phenylpropyl azide (89% yield, 99% purity).

Example 2 Synthesis of (S) -1-phenylpropyl azide 100.0 g of (R) -1-phenylpropyl alcohol in a 1,000 ml four-necked flask equipped with a mechanical overhead stirrer, thermometer and Dimroth condenser
(0.73 mol), diphenylphosphoryl azide 22
2.1 g (0.81 mol) was added, and the mixture was stirred so as to be uniformly mixed. 167.6 g of diazabicycloundecene
(1.10 mol) was added dropwise at 25 ° C. or less over 3 hours,
After dropping, the mixture was aged by stirring at 10 to 25 ° C for 2 hours. After adding 270 ml of isopropyl ether and 330 ml of water, the reaction solution was transferred to a separating funnel and the aqueous layer was separated. Furthermore, water 10
0 ml was added and the organic layer was washed with water. The organic layer after washing was concentrated by removing the isopropyl ether as an extraction solvent using an evaporator, and distilled under reduced pressure (under a pressure of about 5 mmHg and a distillation temperature of about 7).
(2 ° C.) to give (S) -1-phenylpropyl azide 10
8 g was obtained (yield 91%, purity 99%).

Example 3 Synthesis of (S) -1-phenylpropylamine Obtained in Example 1 or Example 2 in a 1,000 ml four-necked flask equipped with a mechanical overhead stirrer, a thermometer, a blowing tube, and a Dimroth condenser. (S)-
100.0 g (0.62 mol) of 1-phenylpropyl azide, 9.0 g (in terms of solids) of palladium carbon and 500 ml of methanol were added, and the mixture was stirred so as to be uniformly mixed. After once replacing the gas phase with a nitrogen gas stream, 19 L (0.85 mol) of hydrogen was blown into the liquid layer at 25 ° C. or lower for 3 hours through a blowing pipe. After blowing, 2 at 10-25 ° C
The mixture was aged by stirring for a period of time. After sufficiently replacing the gas phase with nitrogen again, palladium carbon as a catalyst was separated by filtration. At this time, the filtrate was washed with 30 ml of ethanol. The filtrate was concentrated to remove methanol using an evaporator and distilled under reduced pressure (about 7 mmHg under a distillation temperature of about 70 ° C.) to obtain (S)-.
6-g of 1-phenylpropylamine was obtained (yield 8
2%, purity 99%, 99.5% ee).

Example 4 Synthesis of (S) -1-phenylpropylamine In the same manner as in Example 3, except that ethanol was used as a reaction solvent, (S) -1-phenylpropylamine 6
7.0 g were obtained (yield 80%, purity 99%, 99.5%).
ee).

[0020]

According to the present invention, (R) -1 is used as a starting material.
By using -phenylpropyl alcohol, high-quality (S) -1-phenylpropylamine can be easily, stably and inexpensively produced.

Claims (6)

[Claims] [Claim 1] The following formula (1) (R) -1-phenylpropyl alcohol represented by (1) is reacted with an azidating agent in the presence of a base to give the following formula (2): After generating (S) -1-phenylpropyl azide represented by (2), a hydrogenation reaction is carried out in the presence of palladium carbon, wherein the following formula (3): A method for producing (S) -1-phenylpropylamine represented by (3). 2. (S) -1- represented by the following formula (2).
The method for producing (S) -1-phenylpropylamine according to claim 1, wherein phenylpropyl azide is isolated as an intermediate. Embedded image (2) 3. The method for producing (S) -1-phenylpropylamine according to claim 1, wherein the azidating agent is diphenylphosphoryl azide represented by the following formula (4). Embedded image (4) 4. The method for producing (S) -1-phenylpropylamine according to claim 1, wherein the base is a secondary or tertiary amine. 5. The method for producing (S) -1-phenylpropylamine according to claim 1, wherein the secondary amine according to claim 4 is di-n-butylamine. 6. The tertiary amine according to claim 4, which is triethylamine or diazabicycloundecene.
4. The method for producing (S) -1-phenylpropylamine according to 4.