JPH10120652A - Production of optically active 2-piperidinemethanol - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject compound without impairing its optical activity in short steps using commercially easily available materials by hydrolyzing optically active hexahydro-3H-oxazolo[3,4-a]pyridin-3-one. SOLUTION: This production process comprises the following steps. Optically active N-benzyloxy-carbonylpipecolic acid is reacted with an aluminum hydride compound, e.g. lithium aluminum hydride or a borane compound, e.g. borane- dimethyl sulfide complex in the presence of an acid to form optically active hexahydro-3H-oxazolo[3,4-a]pyridin-3-one. The resultant compound is then mixed with a base, e.g. potassium hydroxide and water, and hydrolyzed at 0-180 deg.C to give the objective optically active 2-piperidinemethanol. The optically active N-benzyloxycarbonylpipecolic acid is a commercially easily available compound.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing optically active 2-piperidinemethanol.

[0002]

2. Description of the Related Art Optically active 2-piperidinemethanol is an important compound as a pharmaceutical intermediate. Conventionally, a method for producing such optically active 2-piperidinemethanol includes:
For example, (1) a method of oxidizing a 1-cyclopentenylmethanol compound using ozone, then reacting the compound with optically active phenethylamine while reducing, and then dephenethylating [Agric. Biol. Chem., 50 , 3107 (1986) )], (2) A multi-step method using an optically active phenylglycine derivative as a starting material and an optically active oxazinone derivative as an intermediate [Heterocycles, 41 , 1931 (1995)].

However, the method (1) is insufficient in that an optically active 2-piperidinemethanol having a low optical purity can be obtained, and the method (2) requires an optically active oxazinone derivative as a starting compound to be obtained industrially. Both methods have problems, for example, compounds that are difficult to perform.

Accordingly, the present inventors have intensively studied to develop a method for producing optically active 2-piperidinemethanol in a short process using a commercially available raw material without impairing the optical purity of the raw material compound. As a result, the optically active hexahydro-3H-oxazolo [3,4- easily obtained from the optically active N-benzyloxycarbonylpipecolic acid
a] By hydrolyzing pyridin-3-one,
Optical activity 2- without easily impairing optical purity
The present inventors have found that piperidine methanol can be produced, and have reached the present invention.

[0005]

That is, the present invention provides a method for producing optically active 2-piperidinemethanol, which comprises hydrolyzing optically active hexahydro-3H-oxazolo [3,4-a] pyridin-3-one. It provides a method.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION Optically active hexahydro-3H-oxazolo [3,4-a] pyridin-3-one used as a starting compound in the method of the present invention is (R) -hexahydro-3H-oxazolo [3, 4-a] pyridin-3-one or (S) -hexahydro-
It may be 3H-oxazolo [3,4-a] pyridin-3-one. These can be easily produced, for example, by reacting an optically active N-benzyloxycarbonyl pipecolic acid which is industrially easily available with an aluminum hydride compound or a borane compound in the presence of an acid.

The optically active N-benzyloxycarbonyl pipecolic acid may be (R) -N-benzyloxycarbonyl pipecolic acid or (S) -N-benzyloxycarbonyl pipecolic acid. The desired optically active hexahydro-3H-oxazolo [3,4-
a] It is appropriately selected and used according to pyridin-3-one.

Examples of the aluminum hydride compound include lithium aluminum hydride and sodium bis (2-methoxyethoxy) aluminum hydride. Examples of the borane compound include a borane-dimethyl sulfide complex, a borane-tetrahydrofuran complex, and an alkali metal borohydride. The amount of the aluminum hydride compound or the borane compound to be used is generally 1 mol times or more, preferably 1 to 5 mol times, relative to the optically active N-benzyloxycarbonylpipecolic acid.

Usually, sulfuric acid, hydrochloric acid, hydrobromic acid,
A mineral acid such as hydrofluoric acid is used, and the amount thereof is usually 0.01 mol times or more, preferably 0.1 to 10 times or more based on the optically active N-benzyloxycarbonylpipecolic acid. However, when an alkali metal borohydride is used as the borane compound, it is usually at least 1 mole times the alkali metal borohydride.

The reaction is usually carried out in a solvent. The solvent is not particularly limited as long as it is inert to the reaction, and examples thereof include ethers such as tetrahydrofuran, diethyl ether and 1,4-dioxane. Solvent, alcoholic solvent such as methanol and ethanol,
Hydrocarbon solvents such as hexane, toluene and benzene,
Examples thereof include halogenated hydrocarbon solvents such as chlorobenzene, dichloromethane, dichloroethane, chloroform, and carbon tetrachloride; aprotic polar solvents such as dimethylformamide; and mixed solvents thereof. The amount of the solvent used is usually in the range of 2 to 50 times by weight based on the optically active N-benzyloxycarbonylpipecolic acid.

The reaction may be carried out, for example, by mixing an optically active N-benzyloxycarbonylpipecolic acid, an acid and an aluminum hydride compound or a borane compound in a solvent. As a borane compound, an alkali metal borohydride and an acid are mixed in the system. In the case of borane produced by the reaction described above, an acid, an alkali metal hydride and an acid may be added to a solvent in advance, and then optically active N-benzyloxycarbonylpipecolic acid may be added. The reaction temperature is usually -50
To 150 ° C, preferably -20 to 100 ° C.

Thus, the optically active hexahydro-3H-oxazolo [3,4-a] pyridin-3-one, which is the starting compound in the method of the present invention, is produced, but is not removed from the reaction mixture after the reaction. It may be used in the method of the present invention, or may be taken out of the reaction mixture and used.

From the reaction mixture after the reaction, optically active hexahydro-3H-oxazolo [3,4-a] pyridine-3-
To remove the ON, for example, a method of adding an aqueous alkali solution such as an aqueous sodium hydroxide solution, followed by extraction using an organic solvent insoluble in water such as chloroform, and a method of distilling off the solvent after washing the obtained organic layer with water. Is mentioned. The obtained optically active hexahydro-3H-oxazolo [3,4-
a] Pyridin-3-one may be further purified by a method such as column chromatography or recrystallization.

Next, in order to hydrolyze optically active hexahydro-3H-oxazolo [3,4-a] pyridin-3-one to produce optically active 2-piperidinemethanol, a base is usually used in the hydrolysis. Examples of such a base include inorganic bases such as alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, and alkaline earth metal hydroxides such as barium hydroxide. Active hexahydro-3H-
It is usually at least equimolar, preferably 1 to 10 times the molar amount of oxazolo [3,4-a] pyridin-3-one. The amount of water used is optically active hexahydro-3H-
It is usually in the range of 2 to 50 times by weight based on oxazolo [3,4-a] pyridin-3-one.

The hydrolysis may be performed in a solvent, or water may be used as a solvent. Examples of such a solvent include the same solvents as described above, and the amount of the solvent to be used is generally 2 to 50 times by weight based on the optically active hexahydro-3H-oxazolo [3,4-a] pyridin-3-one. It is.

The hydrolysis is carried out, for example, by mixing optically active hexahydro-3H-oxazolo [3,4-a] pyridin-3-one, a base and water. Hexahydro-3H-
Oxazolo [3,4-a] pyridin-3-one, a base and water may be mixed. When optically active hexahydro-3H-oxazolo [3,4-a] pyridin-3-one is used as it is in the reaction mixture obtained by the previous reaction, a base and water may be added to the reaction mixture.
The hydrolysis temperature is usually 0 to 180 ° C, preferably 20 to 1 ° C.
It is in the range of 50 ° C.

From the reaction mixture after hydrolysis,
For example, by extracting with a water-insoluble organic solvent such as chloroform and evaporating the obtained organic layer,
The desired optically active optically active 2-piperidinemethanol can be obtained. The extracted organic layer is extracted using an acidic aqueous solution such as dilute hydrochloric acid, and the resulting aqueous layer is made alkaline by adding a base such as sodium hydroxide, and then an organic solvent insoluble in water such as chloroform is used. After extraction by extraction, the obtained organic layer may be subjected to solvent distillation to obtain optically active optically active 2-piperidinemethanol.

[0018]

According to the method of the present invention, an optically active 2-piperidinemethanol can be produced in a short process using a raw material which is industrially easily available, without substantially impairing the optical purity of the raw material compound.

[0019]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.

Example 1 97.4 g (370 mmol) of (R) -N-benzyloxycarbonylpipecolic acid (optical purity: 98.4% ee)
l), 35 g of sodium borohydride (925 mmo
l) and 370 ml of tetrahydrofuran,
After cooling to 1 ° C., 14.4 g of concentrated sulfuric acid (46
3 mmol) in 20 ml of ethyl ether (74 ml).
The mixture was added dropwise over minutes, and then stirred at 25 ° C. for 16 hours. Then, 37 ml of methanol was added dropwise over 15 minutes in an ice bath, concentrated to 300 ml, 370 ml of a 5N aqueous solution of sodium hydroxide was added, extracted with chloroform, and the obtained organic layer was washed with water and then with saturated saline. Then, simple distillation was performed to obtain (R) -hexahydro-3H-oxazolo [3,4-a] pyridin-3-one (36 g, optical purity 98.4% ee) (yield 68.9%). .

Example 2 31.7 g of (R) -hexahydro-3H-oxazolo [3,4-a] pyridin-3-one obtained in Example 1, 28.1 g of potassium hydroxide and 200 ml of water were mixed. The mixture was stirred for 24 hours while heating under reflux. The obtained reaction mixture was extracted with 200 ml of chloroform, and 1
After adding 100 ml of 0% hydrochloric acid, liquid separation was performed to obtain an aqueous layer. 50 ml of a 20% aqueous sodium hydroxide solution was added to this aqueous layer.
Was adjusted to alkaline (pH 9 or more), and extracted with 100 ml of chloroform. The obtained organic layer was evaporated, and (R) -2-piperidinemethanol (19.42 g, optical purity 98) was obtained. 0.4% ee).
(Yield 73.3%)

Claims (9)

[Claims] 1. A process for producing optically active 2-piperidinemethanol, comprising hydrolyzing optically active hexahydro-3H-oxazolo [3,4-a] pyridin-3-one. 2. The method for producing optically active 2-piperidinemethanol according to claim 1, wherein the hydrolysis is carried out using a base. 3. The method according to claim 2, wherein the base is an alkali metal hydroxide or an alkaline earth metal hydroxide.
3. The method for producing optically active 2-piperidinemethanol according to 1.). 4. The amount of base used is optically active hexahydro-3.
3. The method for producing optically active 2-piperidinemethanol according to claim 2, wherein the molar ratio is 1 mol or more of H-oxazolo [3,4-a] pyridin-3-one. 4. 5. An optically active hexahydro-3H-oxazolo [3,4-a] pyridin-3-one is prepared by converting an optically active N-benzyloxycarbonylpipecolic acid into an aluminum hydride compound or a borane compound in the presence of an acid. The method for producing optically active 2-piperidinemethanol according to claim 1, characterized in that it is produced by reacting. 6. The method for producing optically active 2-piperidinemethanol according to claim 5, wherein the acid is a mineral acid. 7. The process for producing optically active 2-piperidinemethanol according to claim 5, wherein the amount of the acid used is 0.01 mol times or more of the optically active N-benzyloxycarbonylpipecolic acid. Method. 8. The optically active compound according to claim 5, wherein the amount of the aluminum hydride compound or the borane compound to be used is at least 1 mole times the optically active N-benzyloxycarbonylpipecolic acid. A method for producing piperidine methanol. 9. An optically active hexahydro-3H-oxazolo [3,4-a] characterized by reacting an optically active N-benzyloxycarbonylpipecolic acid with an aluminum hydride compound or a borane compound in the presence of an acid. A method for producing pyridin-3-one.