JPS5821907B2 - 2- Chikan -5- Aminokitsusou Sanruinoseizouhou - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing 2-substituted-5-aminovaleric acids.

More specifically, the present invention relates to a method for producing novel 2-1-substituted-5-aminovaleric acids by hydrolyzing 3-1-substituted-3-flukoxycarbonyl-2-piperitone.

5-guanidinovaleric acid esters, which can be synthesized from 5-aminevaleric acid, are known as enzyme inhibitors, and can be obtained by esterifying and guanidinating the 2-mono-substituted-5-aminovaleric acids obtained by the method of the present invention. It is expected that the 2-monosubstituted-5-guanidinovaleric acid esters shown in Table 1 also have enzyme inhibitory effects.

For example, the compound represented by the following formula, which is 5-guanidinovaleric acid ester, has a strong antitrypsin effect and is known as a therapeutic agent for pharyngeal inflammation. It serves as the nucleus for the synthesis of analogous compounds having a substituent at the α-position of -COOR of the above-mentioned 5-guanidinovalerate esters.

To explain the present invention in detail, the method of the present invention is represented by the following reaction formula.

The 3-monosubstituted-3-alkoxycarbonyl-2-piperidone, which is the raw material of the method of the present invention, is represented by the above general formula CI), and the 2-monosubstituted-5-aminovaleric acid, which is the product, is represented by the above general formula [■] It is expressed as

In the above formula, R' usually represents an alkyl group having 20 or less carbon atoms, and "usually represents an aralkyl group having 20 or less carbon atoms,
Or represents a phenyl group.

The 3-monosubstituted-3-alkoxycarbonyl-2-piperidone used as a raw material in the present invention is α-substituted-α-(2
-Cyanethyl)malonate ester is catalytically reduced in the presence of a hydrogen-activated catalyst.

The obtained 3-monosubstituted-3-alkoxycarbonyl-2-piperidone is used as a raw material for the method of the present invention without necessarily being isolated and purified.

When 3-4-substituted-3-flucoxycarbonyl-2-piperidone is hydrolyzed, the desired 2-mono-substituted-5-aminovaleric acids can be obtained in good yield through ring cleavage, decarboxylation, and dealcoholization.

Hydrolysis may be carried out using an acid or a base. 3. The detailed hydrolysis method is as follows.

(2) Hydrolysis with acid As the acid, mineral acids such as sulfuric acid, hydrochloric acid, and phosphoric acid are usually used, but strong organic acids such as P-1 luenesulfonic acid are also used.

E is usually used in an amount of 1 equivalent or more per equivalent of 3-4-substituted-3-alkoxycarbonyl-2-piperidone, but in consideration of post-treatment, 1 to 50 equivalents are appropriate.

The reaction temperature is not particularly limited, but is preferably 50 to 20
It is in the range of 0°C.

The reaction time varies depending on the reaction temperature and the type of raw materials, but is usually 10 minutes to 2 hours.

During the reaction, bubbling of carbon dioxide gas is observed, so the completion of the reaction can be determined by the fact that bubbling no longer occurs.

The stoichiometric amount of water required for hydrolysis is 3-substituted-3
The amount is 2 mol per 71 mol of -alkoxycarbonyl-2-piperide.

In order for the reaction to proceed rapidly, 3 to 100
Preferably, twice as much water (by weight) is used.

An organic solvent may be used along with water to increase the solubility of the monosubstituted-3-alkoxycarbonyl-2-piperidone.

As the organic solvent, alcohols such as methanol and ethanol; ethers such as dioxane and tetrahydrofuran are effective.

2. Hydrolysis with a base As the base, common inorganic strong bases such as potassium hydroxide, sodium hydroxide, barium hydroxide, and calcium hydroxide are used.

The amount of alkali used, reaction conditions, etc. are exactly the same as those for acid hydrolysis.

However, when a base is used, no bubbling of carbon dioxide gas is observed.

After the reaction is completed, foaming is observed when neutralized with an acid and treated at a temperature of room temperature to 200°C.

When foaming is no longer observed, the 2-substituted-5-aminovaleric acids are isolated by the general post-treatment shown below.

As the isolation method, a conventional method for isolating general amino acids is employed.

That is, a method of desalting using an ion exchange resin, or a method of desalting an acid or base using an intermediate phase, or an insoluble salt (for example,
BaCO3, Ca5O, CaCO3, AgCl, etc.)
For example, the reaction solvent is removed by filtration and the reaction solvent is distilled off.

Note that if the salt produced by neutralization is soluble in water, concentrating the reaction solution to an appropriate concentration will result in the salt and 2-substituted -5-
A mixture with crystals of aminovaleric acid is obtained.

2-Substituted-5-aminovaleric acid containing impurities such as salts can be purified by recrystallization with water.

The present invention will be specifically explained below with reference to Examples, but the present invention is not limited to the following Examples unless it exceeds the gist thereof.

Example 1 3-phenyl-3-ethoxycarbonyl-2-piperidone 24.7 P (0.1 mol) and a 40% aqueous sulfuric acid solution 3507711 are heated at 110° C. for 4 hours with stirring.

The reaction solution is neutralized with calcium oxide to remove insoluble inorganic substances, the pH of solution F is adjusted to neutral, and the solution is concentrated to obtain a white crystalline residue.

When this residue is dissolved in hot water, treated with activated carbon, and left to stand, colorless crystals of 2-phenyl-5-aminovaleric acid are precipitated.

Melting point: 243-245°C, yield: 17.21 (yield: 89.1
%) Elemental analysis value: 3-(1-naphthylmethyl)-3-ethoxycarbonyl-2-piperidone as C1□H15NO2 15.61 (0.05 mol and 6N
250 ml of an aqueous hydrochloric acid solution is heated at 120°C while stirring for 5 hours.

Concentrate the reaction solution under reduced pressure, add water and dilute with 2N
- When neutralized with aqueous alumonia and heated and allowed to cool, crystals precipitate.

When the P-removed crystals are recrystallized from water, 2-(1-naphthylmethyl)-5-amine valeric acid monohydrate is obtained.

Melting point 178℃, yield 10.5f? (Yield 76.2%: Elemental analysis value: Example as C16H1,NO□・H2O
3 Using 3-(2-(1-naphthyl)ethyl)-3-ethoxycarbonyl-2-piperidone as a raw material and repeating Example 2, 2-(2-(1-naphthyl)ethyl)-5
-Aminovaleric acid% hydrate is obtained.

Melting point: 167°C, yield: 79% Elemental analysis: Ci 7 H
Example 4 as 2□N023AH20 3-benzyl-3-ethoxycarbonyl-2-piperidone 26.1 f! (0.1 mol) and 150 ml of a 2N aqueous sodium hydroxide solution are heated at 95 to 100°C for 6 hours, neutralized with 2N hydrochloric acid, and further heated at 90°C for 1 hour.

When the reaction solution is distilled off, a white residue mixed with common salt is obtained.

Water is added to this residue, heated, and treated with activated carbon to obtain colorless crystals of 2-hensyl-5-aminovaleric acid.

Melting point 215℃, yield 16.21 (yield 78.2%) Elemental analysis value: as C1□H17NO□

Claims (1)

[Scope of Claims] 1 Represented by the following general formula (IJ (in the above general formula CIJ, R' represents an alkyl group having 20 or less carbon atoms, and "represents an aralkyl group or phenyl group having 20 or less carbon atoms.") The following general formula [■] is characterized by hydrolyzing 3-4-substituted-3-alkoxycarbonyl-2-piperidone (in the above general formula [■], Bi is as defined in the general formula CIIJ). A method for producing a 2-substituted 15-aminovaleric acid represented by