BACKGROUND ART The benzyloxyacetaldehyde compound is useful as intermediates of pharmaceuticals for specifically inhibiting proliferation of HIV, a pathogenic virus as disclosed in International Publication W096/10019 (1996).

Conventionally, as a process for preparing the benzyloxyacetaldehyde compound, there have been known a process comprising oxidizing 1-0-benzylglycerol with periodic acid (SYNTHETIC COMMUNICATIONS, 18,359 (1988)); and a process comprising condensing a halogenated acetaldehyde acetal with benzyl alcohol to give benzyloxyacetaldehyde acetal, and hydrolyzing the

resulting benzyloxyacetaldehyde acetal as disclosed in Helv., 33 [1954], 1776,1785.

However, the former process would not be a practical process since the process for preparing the starting material 1-benzylglycerol is quite complicated and expensive periodic acid is required as an oxidizing agent.

The latter process would not also be a practical process since this process necessitates complicated procedures for preparing its intermediate benzyloxyacetaldehyde acetal during the preparation of the benzyloxyacetaldehyde compound from the halogenated acetaldehyde acetal.

An object of the present invention is to provide a process for simply and conveniently preparing a benzyloxyacetaldehyde compound without any expensive oxidizing agents.

DISCLOSURE OF INVENTION According to the present invention, there is provided a process for preparing a benzyloxyacetaldehyde compound represented by the formula (III):

wherein R1 is hydrogen atom or methoxy group, comprising oxidizing a 2-benzyloxyethanol compound represented by the formula (I): wherein R1 is the same as defined above, with a hypochlorite in the presence of an oxyl compound represented by the formula (II): wherein R2 is hydrogen atom, hydroxyl group, acetamino group or methacryloyloxy group.

BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, as a starting material, there can be used a 2-benzyloxyethanol compound represented by the formula (I):

wherein R1 is hydrogen atom or methoxy group.

In the formula (I), R1 is hydrogen atom or methoxy group.

When R1 is methoxy group, R1 may be bonded at any position of 2-, 3-, and 4-positions to-CH2-O-CH2CH20H. Among them, 4-position is preferable.

Typical examples of the 2-benzyloxyethanol compound include 2-benzyloxyethanol, 2- (4-methoxybenzyloxy) ethanol, and the like.

The 2-benzyloxyethanol compound can be prepared by known processes. As one example thereof, for instance, the 2-benzyloxyethanol compound can be prepared by the condensation of a benzyl halide, such as benzyl chloride, with ethylene glycol in the presence of an alkali hydroxide, such as sodium hydroxide as disclosed in Journal of American Chemical Society (JACS), 60,1472 (1938).

When this reaction is employed, there is an advantageous merit in that the resulting 2-benzyloxyethanol compound can be provided for the process of the present invention in the state of a reaction solution without isolating the resulting 2-benzyloxyethanol compound from the reaction solution.

Incidentally, it is preferable that the resulting reaction solution is previously extracted with a solvent such as ethyl acetate and washed.

The oxidation of the 2-benzyloxyethanol compound represented by the formula (I) can be readily carried out in an organic solvent.

The organic solvent is not particularly limited as long as it does not inhibit the oxidation of the 2-benzyloxyethanol compound. Preferable examples thereof are fatty acid esters having 3 to 7 carbon atoms, typically including alkyl acetates having 3 to 7 carbon atoms such as ethyl acetate and butyl acetate; halogenated hydrocarbons such as dichloromethane and dichloroethane; aromatic compounds such as toluene, and the like. Among them, ethyl acetate can be favorably used in the present invention from the aspects of yield, safety and sanitation, and environmental protection. It is preferable that the organic solvent is used together with water to form a two-phase system of organic solvent-water as described below.

It is desired that the amount of the organic solvent is usually 10 to 500 parts by weight or so, preferably 100 to 300 parts by weight or so, based on 100 parts by weight of the 2-benzyloxyethanol compound.

In the present invention, the hypochlorite is used as an oxidizing agent. The hypochlorite includes, for instance, alkali metal hypochlorites such as sodium hypochlorite and potassium hypochlorite; alkaline earth

metal hypochlorites such as calcium hypochlorite, and the like. Among them, sodium hypochlorite can be favorably used in the present invention since its aqueous solution is generally widely marketed and readily available at a low cost.

It is preferable that the amount of the hypochlorite is equal to or greater than the equivalent amount of the 2-benzyloxyethanol compound. When the amount is too large, there is a tendency that a carboxylic acid is generated as a by-product because the resulting benzyloxyacetaldehyde compound is oxidized. Therefore, it is more preferable that the amount of the hypochlorite is 1 to 2 equivalents per one equivalent of the 2-benzyloxyethanol compound.

As the hypochlorite, usually, its aqueous solution, for instance, a marketed aqueous solution can be used.

Incidentally, when the 2-benzyloxyethanol compound is oxidized with the hypochlorite, water is required. When the marketed aqueous hypochlorite is used, no water is required because the aqueous hypochloride contains water in a sufficient amount. It is preferable to use an organic solvent-water two-phase system in which the amount of water is adjusted to 100 to 500 parts by weight, based on 100 parts by weight of the organic solvent from the aspects of operability and yield.

The oxyl compound represented by the formula (II):

wherein R2 is hydrogen atom, hydroxyl group, acetamino group or methacryloyloxy group, can be used as an oxidation catalyst. In the oxyl compound represented by the formula (II), R2 is hydrogen atom, hydroxyl group, acetamino group or methacryloyloxy group. Among them, hydroxyl group and acetamino group are preferable.

It is desired that the amount of the oxyl compound is at least 0.1 mmol, preferably at least 0.5 mmol, per one mol of the 2-benzyloxyethanol compound, from the viewpoints of reaction rates and transfer ratios. In addition, it is desired that the amount of the oxyl compound is at most 3 mmol, preferably at most 1 mmol, from the viewpoints of avoiding the excessive reaction to form a carboxylic acid. The preferable amount of the oxyl compound is 0.1 to 3 mmol, more preferably 0.5 to 1 mmol.

Incidentally, the oxidation of the 2-benzyloxyethanol compound is affected by pH. In the present invention, in order not to be mal-affected when the 2-benzyloxyethanol

compound is oxidized, it is preferable that the pH during the oxidation is adjusted to 8 to 11. The pH adjusting agents which can be used herein includes, for instance, alkali metal carbonates such as sodium hydrogencarbonate, alkali metal phosphates, and the like, but the present invention is not limited to those exemplified ones.

It is desired that the temperature when oxidizing the 2-benzyloxyethanol compound is usually-20° to 100°C or so, preferably 0° to 60°C or so.

In addition, there is no particular limitation as to the atmosphere when oxidizing the 2-benzyloxyethanol compound, and it may be air, or inert gases such as nitrogen gas and argon gas.

The termination of the reaction can be determined, for instance, by confirming the disappearance of the 2-benzyloxyethanol compound using high-performance liquid chromatography. The reaction time is usually 5 to 30 minutes or so.

After the termination of the reaction, the reaction solution is separated into an organic layer and a water layer, from which the organic layer is collected, and the benzyloxyacetaldehyde compound represented by the formula

wherein R1 is the same as defined above, can be isolated therefrom by conventional procedures, including washing, drying, and the like.

Concrete examples of the benzyloxyacetaldehyde compound are benzyloxyacetaldehyde, 4-methoxybenzyloxyacetaldehyde, and the like.

The resulting benzyloxyacetaldehyde compound can be favorably used as intermediates of pharmaceuticals for specifically inhibiting proliferation of HIV, a pathogenic virus as mentioned above.

The present invention will be more specifically described by means of the following examples, without intending to restrict the scope or spirit of the present invention thereto.

Example 1 To a 100 ml four-neck flask were added 18.2 g (0.10 mol) of 2- (4-methoxybenzyloxy) ethanol and 50 g of ethyl acetate, and the temperature inside the flask was adjusted to 5° to 10°C. Thereafter, to the flask were

added 65 g (0.105 mol) of a 12% sodium hypochlorite aqueous solution, 3 g of sodium hydrogencarbonate, and 172 mg (1 mmol) of 4-hydroxy-2,2,6,6- tetramethylpiperidinyl-1-oxy, and the mixture was vigorously stirred with adjusting its pH to 8 to 10.5.

The reaction was monitored by high-performance liquid chromatography. As a result, it was confirmed that the starting material 2- (4-methoxybenzyloxy) ethanol disappeared after 10 minutes.

Subsequently, the resulting solution was allowed to be separated into an organic layer and a water layer. The organic layer was washed with a 5% NaCl aqueous solution and dried over magnesium sulfate. Thereafter, ethyl acetate was distilled off under reduced pressure, to give 16.3 g of 4-methoxybenzyloxyacetaldehyde (yield: 90.5%).

The purity of the resulting 4-methoxybenzyloxyacetaldehyde was confirmed by high-performance liquid chromatography, and found to be 98.1%.

Example 2 To a 500 ml four-neck flask were added 22.8 g (0.15 mol) of 2-benzyloxyethanol and 90 g of ethyl acetate, and the temperature inside the flask was adjusted to 5°C. Thereafter, to the flask were added 95 g (0.153 mol) of a 12% sodium hypochlorite aqueous solution,

4.82 g of sodium hydrogencarbonate, and 240 mg (1.5 mmol) of 4-methacryloyloxy-2,2,6,6-tetramethylpiperidinyl-1-oxy, and the mixture was vigorously stirred with adjusting its pH to 8.5 to 10.1.

The reaction was monitored by high-performance liquid chromatography. As a result, it was confirmed that the starting material 2-benzyloxyethanol disappeared after 15 minutes.

Subsequently, the resulting reaction solution was allowed to be separated into an organic layer and a water layer. The organic layer was successively washed with 20 ml of a 5% sodium hydrogencarbonate aqueous solution and 20 ml of a 5% NaCl aqueous solution, and dried over magnesium sulfate. Thereafter, ethyl acetate was distilled off under reduced pressure, to give 13.8 g of benzyloxyacetaldehyde (yield: 92.0%). The purity of the resulting benzyloxyacetaldehyde was confirmed by high-performance liquid chromatography, and found to be 97.2%.

Example 3 Preparation of 2-Benzyloxyethanol After replacing the atmosphere of 1-liter four-neck flask with nitrogen gas, the flask was charged with 198.7 g (3.2 mol) of ethylene glycol and 46.8 g (0.8 mol)

of sodium hydroxide, and thereto was added dropwise 101.3 g (0.8 mol) of benzyl chloride at 62°C with stirring.

Thereafter, the mixture inside the flask was stirred at a temperature of 80° to 85°C for 3 hours and cooled to 55°C, and thereto was added dropwise 160 ml of water.

Subsequently, the content was neutralized with 35% hydrochloric acid, and 70 g of ethyl acetate was added to the content to allow the separation into an organic layer and a water layer. The organic layer was washed with 40 g of saturated NaCl aqueous solution.

In 187 g of the resulting ethyl acetate solution was contained 95 g of 2-benzyloxyethanol.

Preparation of Benzyloxyacetaldehyde To the ethyl acetate solution obtained above were added a solution prepared by dissolving 16.8 g of sodium hydrogencarbonate and 9.6 g of potassium bromide in 160 ml of water, and 172 mg (1 mmol) of 4-hydroxy- 2,2,6,6-tetramethylpiperidinyl-1-oxy. With vigorous stirring, thereto was added 375 g (0.62 mol) of a 12.4% sodium hypochlorite aqueous solution at 5°C, and its pH was adjusted to be 8 to 10 with vigorous stirring. The reaction was monitored by high-performance liquid chromatography. As a result, it was confirmed that the

starting material 2-benzyloxyethanol disappeared after 15 minutes.

Subsequently, the resulting reaction solution was allowed to be separated into an organic layer and a water layer. The organic layer was successively washed with 50 ml of a 5% sodium hydrogencarbonate aqueous solution and 50 ml of a 5% NaCl aqueous solution, and dried over magnesium sulfate. It was found that 48 g of benzyloxyacetaldehyde was contained in 218 g of the ethyl acetate solution (yield from benzyl chloride: 46%). The purity of the resulting benzyloxyacetaldehyde was confirmed by high-performance liquid chromatography, and found to be 85.7%.

INDUSTRIAL APPLICABILITY As explained above, according to the present invention, the benzyloxyacetaldehyde compound can be simply and conveniently prepared without any expensive oxidizing agents.