JPH0753699B2 - Process for producing 1-alkoxyphenyl-2-amino-1-alcohols - Google Patents

Description

The present invention relates to a method for producing 1-alkoxyphenyl-2-amino-1-alcohols, and more specifically to the general formula (I). (In the formula, R ₁ represents a lower alkyl group or a lower alkoxy group, R ₂ and R ₃ represent a lower alkyl group, and n represents an integer of 0 to 4.) Catalytic hydrogenation in the free state General formula (II) (In the formula, R ₁ , R ₂ , R ₃ , and n have the same meanings as described above.) 1-alkoxyphenyl-2-amino-1-
The present invention relates to a method for producing alcohols.

<Prior Art> 1-alkoxyphenyl-2-amino-1-alcohols are useful as pharmaceuticals and asymmetric ligands in asymmetric reduction (for example, JP-B-36-2176 and JP-A-62-10024). Japanese Patent Laid-Open No. 61-186350), and the following method has been proposed as a method for producing the same.

(A) A method of catalytic hydrogenation of 3,4-dialkoxy-α-oximinopropiophenone under an alkaline alcohol solvent under pressure (US Pat. No. 2,784,228).

(B) 2,5-Dialkoxy-α-oximinopropiophenone produced by catalytic hydrogenation under acidic conditions
A method in which dialkoxy-α-aminopropiophenone hydrochloride is once taken out and purified, and then catalytically hydrogenated using an active catalyst (US Pat. No. 2,359,707).

(C) 2,5-Dialkoxy-α-phthalimido-2,5-dialkoxy-obtained by decomposing propiophenone
A method for reducing Miawein-Ponddorf with α-aminopropiophenone hydrochloride using aluminum isopropoxide (JP-B-36-2176).

<Problems to be Solved by the Invention> However, the method (a) in which the oxyminoketone is catalytically hydrogenated under basic conditions has a drawback that the yield of the target amino alcohol is extremely low, On the other hand, the method (b) of catalytically hydrogenating an oximinoketone under acidic conditions produces a salt of 1-alkoxyphenyl-2-aminoketones and an acid which are hard to undergo hydrogenation (JA).
m.Chem.Soc., 74 , 5927 (1952)), so once separated, it must be subjected to further catalytic hydrogenation using a newly active catalyst, which has the drawback of making the process extremely complicated. It was

In addition, since the above aminoketones have a carbonyl group and an amino group adjacent to each other, since they generate an imine by an intermolecular reaction as they are, they are usually stored and used in the form of a salt with an acid as described above. When this is catalytically hydrogenated, there is a drawback that not only the reaction is slow, but also the erythro / threo ratio of the amino alcohol produced is low, whereas the method of the Myaine-Pond-Lulf reduction (c) has the disadvantage that expensive aluminum isopropoxide is used. However, none of the known methods are industrially sufficiently satisfactory.

<Means for Solving the Problem> In view of the present situation as described above, the present inventors have earnestly studied to find a more excellent production method of 1-alkoxyphenyl-2-amino-1-alcohol, and as a result, It has been found that the desired aminoalcohol can be obtained in a surprisingly high yield and with a high erythro / threo ratio by catalytically hydrogenating the aminoketone represented by the general formula (I) in a free state. The present invention has been completed through studies.

That is, the present invention provides (1) general formula (I) (Wherein R ₁ represents a lower alkyl group or a lower alkoxy group, R ₂ and R ₃ represent a lower alkyl group, and n represents an integer of 0 to 4), and the aminoketone represented by the formula ( ₁ ) is liberated in the presence of a noble metal catalyst. General formula (II) characterized by catalytic hydrogenation in the amine state (In the formula, R ₁ , R ₂ , R ₃ and n have the same meanings as described above.) 1-alkoxyphenyl-2-amino-1-
Method for producing alcohol, and (2) general formula (III) (In the formula, R ₁ , R ₂ , R ₃ and n have the same meanings as described above, and R ₄ represents a hydrogen atom or a lower alkyl group.) The oximinoketone represented by By catalytic hydrogenation to give a compound of general formula (I) (In the formula, R ₁ , R ₂ , R ₃ and n have the same meanings as described above.) A salt of an aminoketone and an acid represented by
Next, the salt is reacted with a base to form a free amine, and then further subjected to catalytic hydrogenation, which is characterized by the general formula (II) (In the formula, R ₁ , R ₂ , R ₃ and n have the same meanings as described above.) 1-alkoxyphenyl-2-amino-1-
The present invention provides a method for producing alcohols.

First, the method (1) will be described.

Examples of the substituent R ₁ of the aminoketone represented by the general formula (I) include lower alkyl groups such as methyl, ethyl, propyl and butyl, and lower alkoxy groups such as methoxy, ethoxy, propoxy and butoxy.

Examples of R ₂ include lower alkyl groups such as methyl, ethyl, propyl and butyl, and examples of R ₃ include lower alkyl groups similar to R ₂ .

More specific compounds include, for example, 2,5-dimethoxy-
α-aminopropiophenone, 2-methyl-4-methoxy-α-aminopropiophenone, 2-methoxy-4-
Methyl-α-aminopropiophenone, 4-methoxy-
α-aminopropiophenone, 2-isopropoxy-α
-Aminopropiophenone 2-methoxy-α-aminopropiophenone, 4-methoxy-α-aminobutyrophenone, 4-methoxy-α-aminovalerophenone, 3,4
-Dimethoxy-α-aminopropiophenone, 3,4-dimethoxy-α-aminobutyrophenone, 3,4-dimethoxy-α-aminovalerophenone, 3,5-dimethyl-4-
Examples of aminoketones include methoxy-α-aminopropiophenone, 2,5-diethoxy-α-aminopropiophenone, 2,4-dimethoxy-α-aminopropiophenone, and 2-ethoxy-α-aminopropiophenone. To be

Since such an aminoketone is usually obtained in the form of a salt with an acid such as hydrochloric acid or sulfuric acid, in this case, a hydrogenation reaction is carried out by adding a base to form a free amine. Examples of the base include alkali hydroxides such as sodium hydroxide and potassium hydroxide, alkali carbonates such as sodium carbonate and potassium carbonate, and alkali alkoxides such as sodium methoxide and potassium ethoxide. The amount used is usually 1.0 to 1.05 equivalents to the acid. Addition in a large excess is not preferable because it causes imine formation between the aminoketone molecules.

As a catalyst for catalytic hydrogenation, a noble metal catalyst such as palladium, platinum, nickel or rhodium is used. The form thereof is preferably a supported type, and among them, a supported type is preferable. The amount of the catalyst used is usually 1 to 25 wt% with respect to the aminoketone of the general formula (I).

As the solvent, a general solvent used for catalytic hydrogenation of ketones can be used, but alcohol solvents such as methanol, ethanol and propanol are preferable. The amount used is usually 2 to 20 wt times the aminoketone.

In carrying out the hydrogenation reaction, heating and pressurization can be performed, but the reaction proceeds sufficiently even at room temperature and atmospheric pressure, and the desired amino alcohol (II) is produced in high yield and with a high erythro / threo ratio. . The desired product can be isolated by a conventional method, and can also be purified by performing recrystallization, distillation, etc. Next, using the oximino ketone represented by the general formula (III) as a starting material (2) The method will be described.

Examples of the substituent R ₄ in the general formula (III) include a hydrogen atom and a lower alkyl group such as methyl, ethyl, propyl and butyl, and R ₁ , R ₂ and R _{3 are the same} as those in the general formula (I). Similar substituents can be mentioned.

When hydrogenating an oximinoketone having such a substituent, hydrochloric acid, sulfuric acid or the like is usually used as an acid, and the amount thereof is usually equal to or more than the amount of oxyminoketone. Examples of the catalyst include noble metal catalysts such as palladium, platinum and rhodium, and the amount thereof is usually 1 to 25 wt% with respect to the oxyminoketone.

As the solvent, a general solvent used for catalytic hydrogenation of ketone is used, but an alcohol solvent such as methanol, ethanol, propanol or the like is preferable. The amount used is usually 2 to 20 wt times the oxyminoketone. The hydrogenation reaction can be carried out under heat and pressure, but at room temperature,
The reaction proceeds sufficiently even under normal pressure, and the reaction spontaneously stops at the stage of absorbing 2 mol times of hydrogen of oxyminoketone.

Thus, a salt of aminoketone (I) and an acid is formed,
After taking out this salt once, catalytic hydrogenation may be carried out by the above-mentioned method (1). Alternatively, without taking out the salt, a base is directly added to the reaction mass to convert the salt into a free amine state. By doing so, the hydrogenation reaction restarts,
This method may be adopted.

In the latter case, as the base, the same bases as in the method (1) can be mentioned. The amount used is equivalent to or more than the acid used in the previous step, and the excess amount is usually 0.05 equivalent or less to the aminoketone (I). Further, the reaction proceeds sufficiently even at room temperature and atmospheric pressure as in the method (1), and the desired amino alcohol (II) is produced in a high yield and a high erythro / threo ratio. The desired product can be isolated and purified by a conventional method.

<Effect of the Invention> Thus, the desired amino alcohol (II) is produced. According to the present invention, a high yield and a high erythro /
The target product with a threo ratio is obtained.

When oximinoketone (III) is used as a starting material,
The desired aminoalcohol (II) can be produced all at once without taking out the intermediate aminoketone (I) out of the system, and the reaction process can be simplified.

<Examples> Hereinafter, the present invention will be described in detail with reference to Examples, but the present invention is not limited thereto.

Example 1 (1-1) Preparation of 2,5-dimethoxy-α-aminopropiophenone hydrochloride 2,5-dimethoxy-α-oxyminopropiophenone 1.0
Dissolve 1 g in 10 ml of methanol and then add 1.2 ml of 36% hydrochloric acid, 5
% Platinum-carbon 0.15 g was added, and hydrogenation was carried out at room temperature under normal pressure using a normal pressure catalytic hydrogenation apparatus, and hydrogen absorption stopped after 1.5 hours. The amount of absorbed hydrogen was 204 ml.

After passing the catalyst through the reaction mass, the solvent was distilled off under reduced pressure, and then 20 ml of water and 10 ml of ether were added for extraction. The aqueous layer was separated, and a 20% aqueous sodium hydroxide solution was added thereto to make it alkaline, and then 20 ml of chloroform was added for extraction. The organic layer was separated, concentrated under reduced pressure, and dissolved in 10 ml of methanol. Next, 36% hydrochloric acid was added to form a hydrochloride, and the solvent was evaporated under reduced pressure. The solid obtained is washed with 10 ml of acetone,
After drying, 1.09 g of 2,5-dimethoxy-α-aminopropiophenone hydrochloride was obtained.

Yield 98%, melting point 172-173 ° C. (1-2) Preparation of 1- (2,5-dimethoxyphenyl) -2-amino-1-propanol 2,5-dimethoxy-α-amino obtained in 1-1 Dissolve 0.56 g of propiophenone hydrochloride in 5 ml of methanol, add 0.3 ml of 0.093 g of sodium hydroxide to make it a free amine, and then add 0.095 g of 5% platinum-carbon and hydrogen at room temperature and atmospheric pressure. Was made. After 3 hours, the reaction stopped by absorbing 56 ml of hydrogen.

After removing the catalyst, 0.3 ml of 36% hydrochloric acid was added to give a hydrochloride, and the solvent was distilled off. The solid obtained in 10 ml of acetone
Washed with water, dried and dried with 1- (2,5-dimethoxyphenyl)
0.54 g of 2-amino-1-propanol hydrochloride (yield 95
%) Was obtained. As a result of analysis by liquid chromatography, the erythro / threo ratio was 95/5.

Example 2 2,5-dimethoxy-α-oximinopropiophenone 0.5
g was dissolved in 5 ml of methanol, and then 36% hydrochloric acid 0.6 ml, 5%
When platinum-carbon (0.05 g) was added and the reaction was conducted under hydrogen at room temperature and atmospheric pressure, hydrogen absorption stopped after 1.5 hours. Hydrogen absorption is 1
It was 08 ml. When a solution of 0.29 g of sodium hydroxide and 0.6 ml of water was added to the reaction solution, hydrogen absorption started again and 55 ml of hydrogen was absorbed in 4 hours.

After removing the catalyst, 0.3 ml of 36% hydrochloric acid was added, the solvent was distilled off under reduced pressure, and then 15 ml of water and 10 ml of ether were added for extraction. The aqueous layer was separated, 5 ml of 20% aqueous sodium hydroxide solution was added thereto, and the mixture was extracted once with 20 ml of chloroform and once with 10 ml. The obtained chloroform layers were combined and concentrated under reduced pressure, and then 10 ml of methanol and 0.2 ml of 36% hydrochloric acid were added to give a hydrochloride, and then the solvent was distilled off under reduced pressure. The obtained solid was washed with 10 ml of acetone, dried, and 1- (2,5-dimethoxyphenyl) -2-amino-1-propanol hydrochloride 0.50 g.
(Yield 90%) was obtained. The erythro / threo ratio was 97/3.

Example 3 The procedure of Example 2 was repeated, except that 0.1 g of 5% palladium-carbon was used instead of 5% platinum-carbon in Example 2.
1- (2,5-dimethoxyphenyl) -2-amino-1-
0.4 g of propanol hydrochloride (yield 72%) was obtained. The erythro / threo ratio was 94/6.

The reaction in the first step stopped after absorbing 106 ml of hydrogen in 2 hours. In the second reaction, 45 ml of hydrogen was absorbed 7 hours after the addition of the sodium hydroxide aqueous solution.

Example 4 Example 2 was repeated except that 0.05 g of 5% rhodium-carbon was used, and 1- (2,5-dimethoxyphenyl) -2-amino-1-propanol hydrochloride was added.
53 g (96% yield) were obtained. The erythro / threo ratio was 97/3.

Incidentally, the reaction in the first step stopped after absorbing 110 ml of hydrogen in 3.5 hours. In the second reaction, 57 ml of hydrogen was absorbed within 2 hours after the addition of the sodium hydroxide aqueous solution.

Examples 5-8 In Example 2, instead of 2,5-dimethoxy-α-oximinopropiophenone, 2-methyl-4-methoxy-
α-Oxyminopropiophenone, 4-methoxy-α-oximinovalerophenone, 2-methoxy-4-methyl-
α-Oxyminopropiophenone, 2,5-dimethoxy-
5 using α-methoxyminopropiophenone
Example 2 was repeated except that 0.15 g of% platinum carbon was used. The results are shown in Table 1.

Comparative Example 1 0.51 g of 2,5-dimethoxy-α-aminopropiophenone hydrochloride obtained in 1-1 was dissolved in 5 ml of water, 0.15 g of 5% platinum-carbon was added, and hydrogenated at room temperature and atmospheric pressure. As a result, 60 ml of hydrogen was absorbed in 3 hours. The same post-treatment as in 1-1 was carried out to obtain 0.49 g (yield 95%) of 1- (2,5-dimethoxyphenyl) -2-amino-1-propanol hydrochloride. The erythro / threo ratio was 88/12.

Comparative Example 2 When hydrogenation was started in the same manner as in Example 2 except that 0.125 g of 5% palladium-carbon was used instead of 5% platinum carbon in Example 2, 102 ml of hydrogen was absorbed in 2 hours, and Absorption has stopped.

When it was then heated to 50 ° C., 38 ml of hydrogen was absorbed in 7 hours. Post-treatment was carried out in the same manner as in Example 2 to obtain 0.37 g (yield 67%) of 1- (2,5-dimethoxyphenyl) -2-amino-1-propanol hydrochloride. Erythro / threo ratio is 85 /
It was 15.

Claims (2)

[Claims] 1. A general formula (I) (In the formula, R ₁ represents a lower alkyl group or a lower alkoxy group, R ₂ and R ₃ represent a lower alkyl group, and n represents an integer of 0 to 4.) The aminoketone represented by General formula (II) characterized by catalytic hydrogenation in the state of (In the formula, R ₁ , R ₂ , R ₃ and n have the same meanings as described above.) 1-alkoxyphenyl-2-amino-1-
Method for producing alcohol. 2. General formula (III) (In the formula, R ₁ represents a lower alkyl group or a lower alkoxy group, R ₂ and R ₃ represent a lower alkyl group, R ₄ represents a hydrogen atom or a lower alkyl group, and n represents an integer of 0 to _4. ) The oxyminoketone represented by the formula (I) is subjected to catalytic hydrogenation in the presence of a noble metal catalyst under acidic conditions, (In the formula, R ₁ , R ₂ , R ₃ and n have the same meanings as described above.) A salt of an aminoketone and an acid represented by
Next, the salt is reacted with a base to form a free amine, and then further subjected to catalytic hydrogenation, which is characterized by the general formula (II) (In the formula, R ₁ , R ₂ , R ₃ and n have the same meanings as described above.) 1-alkoxyphenyl-2-amino-1-
Method for producing alcohol.