JPH05255204A - Production of amines - Google Patents

Abstract

PURPOSE:To easily obtain an amine having various physiological activities at a low cost by the decarbonation reaction of an easily available amino acid, etc., abundantly existing in nature in the presence of a catalyst easily available on an industrial scale at a low cost and having excellent stability. CONSTITUTION:An amine is easily produced in high yield by using a carboxylic acid having amino group as a starting raw material and subjecting the acid to decarbonation reaction at about 100-250 deg.C (preferably about 140-170 deg.C) in the presence of a monoaryl ketone catalyst expressed by formula (R<1> is substituted or unsubstituted aryl; R<2> is substituted or unsubstituted alkyl; R<1> and R<2> may be bonded together to form a ring). The amount of the catalyst is preferably 1-20mol%, especially 3-10mol% based on the starting raw material to facilitate the purification of the product. A steric isomer such as optical isomer can be used as the starting raw material without influencing the reaction and the reaction proceeds while keeping the original steric configuration to obtain an optically active amine.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for producing amines by decarboxylation of carboxylic acids having an amino group.

Amines have various physiological activities and are important as industrial raw materials. Particularly, those having various functional groups in the side chains and optically active amines have been remarkably increasing in importance as raw materials for medicines, agricultural chemicals and the like in recent years.

According to the production method of the present invention, the useful amines as described above are naturally present in a large amount and can be easily produced at a low cost using easily available amino acids and the like as raw materials.

[0004]

2. Description of the Related Art Generally, the decarboxylation reaction of a compound is carried out by heating strongly. However, except for a compound having a specific structure which is easily decarboxylated, it is heated at a considerably high temperature for a long time. In many cases, harsh conditions are required. In order to avoid this, there are some examples where the reaction is carried out in the presence of a catalyst such as a peroxide or a copper salt, but these catalysts are not desirable in industrial production in terms of their danger, waste disposal, etc. Magazine, 85, 1965, page 531, U.S. Pat. No. 4,262,157).

In order to solve these problems, the method described in JP-A-60-23328 is a very useful method for industrial production in which vinyl ketones are used as catalysts because they are easy to handle and the post-treatment of the reaction is simple. However, there are other problems that it is difficult to obtain vinyl ketones used as a catalyst on an industrial production scale, and the stability is not good.

As a result of intensive studies to solve the above problems, the present inventors have found that the decarboxylation reaction of aryl ketones, which is inexpensive, can be stably obtained even on an industrial production scale, and is excellent in stability. It was found that the present invention is useful as a catalyst for the above, and that amines can be produced in good yield by using this catalyst, and has completed the present invention.

[0007]

The present invention uses a carboxylic acid having an amino group as a starting material and has the general formula (I):

[0008]

[Chemical 2]

(In the formula, R ¹ represents a substituted or unsubstituted aryl group, R ² represents a substituted or unsubstituted alkyl group, and R ¹ and R ² may be bonded to each other to form a ring. Good)
The present invention relates to a method for producing amines, which comprises carrying out a decarboxylation reaction in the presence of a monoarylketone catalyst.

[0010]

ACTIONS AND EXAMPLES According to the production method of the present invention, the starting material effectively undergoes a decarboxylation reaction to obtain the desired amines. As the starting material, any carboxylic acid having an amino group may be used without particular limitation. Specific examples of the starting material include α having an alkyl or aryl side chain such as glycine, alanine, phenylalanine, leucine, isoleucine, valine, and phenylglycine.
-Including amino acids, threonine, serine, tyrosine, p-hydroxyphenylglycine, asparagine, aspartic acid, glutamic acid, lysine, arginine, histidine, ornithine, tryptophan, cysteine, cysteine, side chain hydroxyl group, carboxyl group, Α-Amino acids having a basic functional group, a functional group containing sulfur, etc., and cyclic α-amino acids such as proline and hydroxyproline are particularly preferable. Further, derivatives of these and other substituents may be used. You may use the compound which has.

Even if the starting material is a stereoisomer, for example, an optical isomer, it does not affect the reaction at all, and the reaction proceeds while maintaining the original configuration, resulting in an optically active amine. You can get the kind.

The aryl ketones used as a catalyst in the present invention have the general formula (I):

[0013]

[Chemical 3]

(In the formula, R ¹ represents a substituted or unsubstituted aryl group, R ² represents a substituted or unsubstituted alkyl group, and R ¹ and R ² may be bonded to each other to form a ring. Good)
It is a monoaryl ketone represented by.

Examples of R ¹ include a phenyl group;
At least one alkyl group, preferably 1 to 4 carbon atoms
Alkyl group, alkoxy group, preferably having 1 to 4 carbon atoms
And an alkoxy group, an amino group, a nitro group, a substituted phenyl group substituted with a halogen atom, and the like. In the substituted phenyl group, the position of the substituent is o-position, m-position,
The p-position (2, 3, 4, 5, 6) or a combination thereof can be arbitrarily selected. Specific examples of R ¹ include a methylphenyl group, an ethylphenyl group, a dimethylphenyl group, a methoxyphenyl group, a dimethoxyphenyl group, a chlorophenyl group, an aminophenyl group and a nitrophenyl group.

The R ² is, for example, 1 to 5 carbon atoms.
And alkyl groups, and specific examples thereof include a methyl group, an ethyl group, a propyl group and a butyl group.

When R ¹ and R ² are combined to form a ring, they are selected from groups in which R ¹ and R ² in the general formula (I) are combined to form a ring without particular limitation.

Specific examples of the monoaryl ketone represented by the general formula (I) include alkyl aryl ketones such as acetophenone, propiophenone and butyrophenone, p-methylacetophenone, o-methylacetophenone, p-ethylacetophenone, 2,4-dimethylacetophenone, 3,4-dimethylacetophenone, p-methoxyacetophenone, 3,4-dimethoxyacetophenone,
Substituted or unsubstituted compounds such as 2,4-dimethoxyacetophenone, 2,3-dimethoxyacetophenone, p-chloroacetophenone, p-aminoacetophenone and p-nitroacetophenone, which are generally called substituted aryl ketones, and α- Examples thereof include, but are not limited to, cyclic aryl ketones such as tetralone.

The amount of the catalyst used is preferably 1 to 20 mol% and more preferably 3 to 10 mol% with respect to the starting material from the viewpoint of easy purification.

The decarboxylation reaction in the present invention may be carried out in the absence of a solvent, but it is suitable considering the solubility of the starting materials and the reaction product for the reasons that the reaction can proceed uniformly and the reaction temperature can be easily controlled. It is preferable to carry out in the presence of a different solvent. As the solvent, any inert solvent that does not participate in the reaction can be used without particular limitation. Specific examples thereof include alcohols such as octanol, heptanol, hexanol, cyclohexanol, and cycloheptanol, hydrocarbons such as tetralin, octaline, and dihydronaphthalene, and ketones such as cyclohexanone and cycloheptanone. Alcohols are preferable in terms of reaction temperature, yield, and the like.

In the decarboxylation reaction of the present invention, after the starting material, the catalyst and the solvent used as appropriate are charged, the starting material is consumed under a suitable temperature condition selected depending on the material and the solvent, preferably under a nitrogen stream. Stir until
It is preferable to complete the reaction.

The reaction temperature may be selected at an arbitrary temperature of about 100 to 250 ° C, but is preferably about 140 to 170 ° C in industrial production.

By selecting the appropriate conditions described above, the reaction proceeds at a high rate and the desired amines are synthesized in a high yield, so that the desired amines can be easily isolated after the reaction. For example, a highly pure product is obtained by a method such as crystallization as an appropriate acid salt, distillation, or crystallization as it is using a poor solvent. If necessary, column chromatography, recrystallization or the like is used. It may be purified.

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

Example 1 (Synthesis of 3- (R) -hydroxypyrrolidine) 100 g of 4- (R) -hydroxy-L-proline, 10 g of p-methylacetophenone and 500 ml of cyclohexanol were added to give a suspension of 150. The mixture was vigorously stirred under a nitrogen stream at about 160 ° C. After 2 hours, the reaction solution in which crystals disappeared and became uniform was cooled to around room temperature, 500 ml of toluene was added, and further cooled to 5 ° C. When dry hydrogen chloride gas was blown into this solution while being careful not to let the internal temperature rise above 15 ° C, crystals were precipitated. After stirring the obtained slurry liquid at 5 ° C. for 1 hour, the crystals were collected by filtration with a glass filter. The obtained crystals were washed with 500 ml of toluene and dried in a vacuum drier to obtain 81.5 g of the desired compound as a hydrochloride salt (yield 86%).

By measuring the optical purity of this product by HPLC, it was confirmed that the configuration at the 3-position was R, the absolute configuration of the starting material was maintained in this reaction, and racemization did not occur. The NMR spectrum, melting point and specific rotation of the obtained compound are shown below.

Nmr (d ₆ -DMSO, 90MHz) δ (ppm): 1.8-1.9 (2H, m), 3.0-3.3 (4H, m), 4.
4 (1H, m), 7.0-8.0 (2H, broad) mp 109-110 ℃

[0028]

[Equation 1]

Example 2 (Synthesis of 3- (R) -hydroxypyrrolidine) A suspension containing 150 g of 4- (R) -hydroxy-L-proline, 270 mg of p-methoxyacetophenone and 25 ml of cyclohexanol was added. The mixture was vigorously stirred under a nitrogen stream at around 160 ° C. After 2 hours, the reaction solution in which the crystals disappeared and became uniform was treated in the same manner as in Example 1 to obtain 4.1 g of the desired compound as a hydrochloride (yield 87%). The obtained compound was confirmed in the same manner as in Example 1.

Example 3 (Synthesis of 3- (R) -hydroxypyrrolidine) In place of p-methoxyacetophenone, 340 mg of 3,4-dimethoxyacetophenone was added and the same procedure as in Example 2 was carried out to obtain the desired compound. Was obtained as a hydrochloride (yield 85%). The obtained compound was confirmed in the same manner as in Example 1.

Example 4 (Synthesis of 3- (R) -hydroxypyrrolidine) Propiophenone (260 mg) was added instead of p-methoxyacetophenone, and the same procedure as in Example 2 was carried out to give the target compound as a hydrochloride salt. As 3.8 g (yield
81%). The obtained compound was confirmed in the same manner as in Example 1.

Example 5 (Synthesis of 3- (R) -hydroxypyrrolidine) α-tetralone instead of p-methoxyacetophenone
By adding 550 mg and performing the same operation as in Example 2, 4.3 g of the target compound was obtained as a hydrochloride (yield 91
%). The obtained compound was confirmed in the same manner as in Example 1.

Example 6 (Synthesis of 3- (R) -hydroxypyrrolidine) 260 mg of 3-aminoacetophenone or 4-aminoacetophenone was added instead of p-methoxyacetophenone,
By carrying out the same operation as in Example 2, 4.0 g of the target compound was obtained as a hydrochloride in each case (yield 85%).
The obtained compounds were confirmed in the same manner as in Example 1.

Example 7 (Synthesis of 1-amino-2- (R) -propanol) A suspension of 10 g of L-threonine and 1.28 g of α-tetralone with 50 ml of cyclohexanol was added at about 150 to 160 ° C. Stir vigorously under a stream of air. After 4 hours, the reaction solution in which the crystals disappeared and became uniform was cooled to around 50 ° C., and 8.0 g of oxalic anhydride dissolved in 100 ml of ethyl acetate was added. The resulting slurry was cooled to room temperature and stirred for 1 hour, then filtered through a glass filter and washed with 2 × 50 ml of ethyl acetate.
Washed twice. The obtained crystals are dried at 50 ° C for 5 hours with a vacuum pump to give the target compound, a heavy oxalate salt of 13.04.
g was obtained (94% yield). The NMR spectrum, melting point and specific rotation of the obtained product are shown below.

Nmr (d ₆ -DMSO, 90MHz) δ (ppm): 1.1 (3H, d), 2.6 (1H, dd), 2.8 (1
H, dd), 3.8 (1H, m), 7.9-8.3 (1H, broad) mp 138-140 ℃

[0036]

[Equation 2]

Example 8 (Synthesis of Histamine) To 25.4 g of L-histidine and 2.35 g of α-tetralone,
Add a suspension containing 125 ml of cyclohexanol to 150-160.
The mixture was vigorously stirred under a nitrogen stream at around ℃. After continuing heating and stirring for 1 day, the reaction solution in which crystals disappeared and became uniform was cooled to around room temperature, 250 ml of toluene was added, and 12.0 g of hydrochloric acid gas was blown in while cooling to 10 ° C. Then, the slurried solution was stirred for 1 hour while being cooled, filtered by a glass filter, washed 3 times with 20 ml of toluene, and dried by a vacuum pump at 40 ° C. for 6 hours to obtain the target compound 2
8.3 g was obtained (yield 94%). The NMR spectrum and melting point of the obtained compound are shown below.

Nmr (d ₆ -DMSO, 90MHz) δ (ppm): 3.1-3.7 (4H, d), 7.5 (1H, d), 8.8
(1H, d) mp 252-254 ℃

[0039]

EFFECTS OF THE INVENTION According to the production method of the present invention, amines can be easily produced by decarboxylation reaction from amino acids and the like which are naturally present in large amounts and are easily available.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Office reference number FI technical display location C07D 207/12 7019-4C 233/64 105 // C07B 61/00 300

Claims (1)

[Claims] 1. Using a carboxylic acid having an amino group as a starting material, the compound represented by the general formula (I): (In the formula, R ¹ represents a substituted or unsubstituted aryl group,
R ² represents a substituted or unsubstituted alkyl group, and R ¹ and R
⁽² may combine with each other to form a ring), and the decarboxylation reaction is carried out in the presence of a monoarylketone catalyst.