JP2001139510A - Method for producing 2-benzyloxyacetaldehyde dialkyl acetal - Google Patents

Abstract

(57) [Problem] To provide an industrially useful method for producing 2-benzyloxyacetaldehyde dialkyl acetal. SOLUTION: Benzyl alcohol is reacted with 2-haloacetaldehyde dialkyl acetal in the presence of a metal hydroxide having an apparent specific gravity of 0.9 to 1.3 g / cc.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing 2-benzyloxyacetaldehyde dialkyl acetal, which is useful as an intermediate for pharmaceuticals such as anti-AIDS agents.

[0002]

2. Description of the Related Art As a method for producing 2-benzyloxyacetaldehyde dialkyl acetal, JACS, 77 ,
6391 (1955) contains sodium benzylate and 2
-A method for reacting chloroacetaldehyde dimethyl acetal is disclosed in Agric. Biol. Chem. , 4
7 , 2677 (1983) describes a method of reacting benzyl alcohol with 2-bromoacetaldehyde diethyl acetal in the presence of sodium hydride.

[0003]

However, with such a technique, although the yield of the desired product can be satisfied, it is necessary to use a chemical such as sodium benzylate and sodium hydride which is extremely difficult to handle industrially, and this requires industrial use. It is hardly adopted for implementation on a scale. Under such technical background, the present inventor tried to use metal hydroxide which is easy to handle in place of the above-mentioned chemicals, but the scale adheres to the reaction system, causing production troubles or reducing the yield. do it,
It was not satisfactory.

[0004]

The present inventor has further studied and found that the apparent specific gravity was 0.9 to 1.3 g / g.
By reacting benzyl alcohol with 2-haloacetaldehyde dialkyl acetal in the presence of cc metal hydroxide, it is found that 2-benzyloxyacetaldehyde dialkyl acetal can be produced industrially easily and with a yield comparable to that of the conventional method. As a result, the present invention has been completed.

[0005]

BEST MODE FOR CARRYING OUT THE INVENTION The reaction of the present invention is represented by the following formula (1).

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Here, X is a halogen, specifically chloro or bromo, and R is an alkyl group, preferably a methyl, ethyl, propyl or butyl group. Examples of the 2-haloacetaldehyde dialkyl acetal that can be advantageously used in the present invention include 2-chloroacetaldehyde dimethyl acetal, 2-chloroacetaldehyde diethyl acetal, 2-bromoacetaldehyde dimethyl acetal, and 2-bromoacetaldehyde diethyl acetal.

In the present invention, the apparent specific gravity as an alkali during the reaction is 0.9 to 1.3 g / cc, preferably 1.0 to 1.3 g / cc.
The use of 1.2 g / cc metal hydroxide is a significant feature. Examples of the metal include alkali metals and alkaline earth metals. Representatively, sodium hydroxide, potassium hydroxide and the like can be suitably used. The apparent specific gravity is 0.9g /
When the metal hydroxide is less than cc, scale is generated in the reaction system, which is likely to cause inconvenience in the production process, and the yield of the target product is lowered to be impractical. On the other hand, the apparent specific gravity is 1.3 g / cc.
Exceeding the limit may cause a problem that fine powder may be scattered and workability may be degraded, which is not practical. The shape of the metal hydroxide may be pearls, pellets, flakes, or the like, and the particle size is practically about 0.5 to 1.0 mm.

In carrying out the reaction, a solvent, a metal hydroxide, benzyl alcohol and a 2-haloacetaldehyde dialkyl acetal are charged into a reactor and heated. The means for charging all the medicines used in the present invention is optional, and any of batch charging, divided charging, continuous charging, drop charging and the like can be performed, but batch charging is particularly advantageous.

The solvent is not particularly limited, but specific examples thereof include ketones such as acetone and methyl isobutyl ketone, esters such as ethyl acetate, halogenated hydrocarbons such as ethylene dichloride, benzene, xylene, and toluene. And aliphatic and alicyclic hydrocarbons such as pentane, hexane and cyclohexane.

The raw materials are used in an amount of 0.5 to 2 moles, preferably 0.8 to 1.2 moles of 2-haloacetaldehyde dialkyl acetal and 0.5 to 2 moles of metal hydroxide per mole of benzyl alcohol. 3 mol, preferably 0.9 to 2.0 mol is suitable. The solvent is used in an amount of 0.5 to 5 times the weight of benzyl alcohol. The reaction temperature may be any number of times, but preferably from 60 to 150 ° C.

In the reaction, it is advantageous in terms of yield to remove by-produced water out of the system, preferably to continue the reaction while azeotropically dehydrating with a solvent. After completion of the reaction, water is added to the reaction product solution, and the mixture is allowed to stand. Then, two layers are separated into an organic layer in which the target substance is dissolved and an aqueous layer in which impurities are dissolved. The organic layer is used as it is or after being concentrated for the next step. If necessary, further purification such as distillation is performed.

[0012]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below in detail with reference to examples.
“%” Is based on weight. Example 1 2-chloroacetaldehyde dimethyl acetal 249
g (2.0 mol), benzyl alcohol 259.2 g
(2.4 mol), pearl-like sodium hydroxide [apparent specific gravity 1.1 g / cc, particle size 0.7 mm] 121 g (3.0
Mol) and 259 ml of toluene were charged all at once into a reactor, and the reaction was carried out for 18 hours while azeotropically dehydrating under reflux (105 ° C.).

After completion of the reaction, the reaction solution is cooled to room temperature and
After adding 00 g, the mixture was left to separate into two layers. The toluene layer was separated, and a toluene extract from the aqueous layer was further mixed with the toluene layer. Analysis of the toluene layer revealed that the yield of 2-benzyloxyacetaldehyde dimethyl acetal was 81%. Infrared analysis of the main fraction obtained by distilling this product,
As a result of NMR analysis, 2-benzyloxyacetaldehyde dimethyl acetal was confirmed.

Example 2 The same reaction as in Example 1 was carried out except that 2-chloroacetaldehyde dimethyl acetal was used and 2-bromoacetaldehyde diethyl acetal was used as a raw material. 2-
Benzyloxyacetaldehyde diethyl acetal was obtained with a yield of 80%.

Control Example 1 In Example 1, the alkali had an apparent specific gravity of 0.75 as an alkali.
The reaction was carried out according to the same example using sodium hydroxide pellets having a particle size of 0.7 mm and g / cc, and scale was attached to the system during the reaction. By this reaction, 2-benzyloxyacetaldehyde dimethyl acetal was obtained with a yield of 71%.

[0016]

According to the present invention, 2-benzyloxyacetaldehyde dialkyl acetal, which is useful as an intermediate for pharmaceuticals such as anti-AIDS agents, has an apparent specific gravity of 0.9 to 1.3 g /
By reacting benzyl alcohol with a 2-haloacetaldehyde dialkyl acetal in the presence of cc of a metal hydroxide, it can be obtained industrially easily and with a yield comparable to that of the conventional method.

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Claims (4)

[Claims] 1. A 2-benzyloxyacetaldehyde dialkyl comprising reacting benzyl alcohol with a 2-haloacetaldehyde dialkyl acetal in the presence of a metal hydroxide having an apparent specific gravity of 0.9 to 1.3 g / cc. Acetal production method. 2. The method for producing 2-benzyloxyacetaldehyde dialkyl acetal according to claim 1, wherein sodium hydroxide is used as the metal hydroxide. 3. The method for producing a 2-benzyloxyacetaldehyde dialkyl acetal according to claim 1, wherein 2-chloroacetaldehyde dimethyl acetal is used as the 2-haloacetaldehyde dialkyl acetal. 4. The reaction according to claim 1, wherein the reaction is carried out while removing by-product water in the reaction system to the outside of the system.
-A method for producing benzyloxyacetaldehyde dialkyl acetal.