JPS61137852A - Production of carrobenzyloxyacetamidine - Google Patents

Abstract

PURPOSE:To produce a carbobenzyloxyacetamidine, in high selectivity, purity and yield, by reacting a benzyl chloroformate compound with an acetamidine mineral acid salt under specific condition. CONSTITUTION:The objective compound can be produced by reacting a benzyl chloroformate compound (abbreviated as BYCF) with an acetamidine mineral acid salt (abbreviated as ATD). The reaction is carried out at -20-+20 deg.C, preferably -10-+10 deg.X for 1-20hr keeping the pH of the reaction system to >=12, by using an aqueous solution of ATD and if necessary an organic solvent such as methylene dichloride, etc., as the base liquid, and supplying BYCF or its organic solvent solution slowly to the mixture. The amounts of the caustic alkali is 1.3-2.0mol per 1mol of ATD.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to a method for producing carbobendiyloxyacetamidines (hereinafter referred to as CBZ-AA).

(Prior art) For example, N-p-nitrocarbobendiyloxyacetamidine is produced by combining p-nitrobenzyl chloroformate and acetamidine mineral salt (hereinafter referred to as ATD) in the presence of a caustic alkali according to the following reaction formula. It can be produced by the following reaction.

This reaction of p-nitrobenzyl chloroformate ATD can be carried out in a mixed solvent of water and an organic solvent, but benzyl chloroformates such as p-nitrobenzyl chloroformate (hereinafter referred to as BYCF) Generally, it is easily decomposed by caustic alkali, so
A method is adopted in which the raw material components BYOF and ATD are used as a bedding solution, and a reaction is carried out while supplying caustic alkali to this solution.

(Problems with the prior art) However, when the synthesis reaction of CBZ-AA such as N-p-erbopendiyloxyacetamidine is carried out in this way, it is difficult to select the target compound 0BZ-A'A. The drawback is that the yield is low, and therefore it is difficult to recover high-purity products with low yields. In particular, 0
In the case of a reaction in which BZ-AA precipitates as crystals, if a large amount of by-products are contained in the crystals, a special purification treatment is required, and the purification is also not easy.

The present invention aims to provide a method for synthesizing 0BZ-AA with high selectivity and obtaining a high-purity product in good yield when producing CBZ-AA by reacting BYOF and ATD in the presence of caustic alkali. purpose.

(Means for Solving the Problems) That is, the gist of the present invention is to provide a method for producing 0BZ-AA by reacting BYCF and ATD in a water-organic solvent in the presence of caustic alkali. CBZ characterized in that the reaction is carried out with an aqueous solution of caustic alkali and, if necessary, an organic solvent as a bedding liquid, while gradually supplying BYCFF or its organic solvent solution.
-It consists in the manufacturing method of AA.

In the present invention, CBZ-AA is produced by reacting BYCFF and ATD in a water-organic solvent in the presence of caustic alkali. Specific examples include p-nitropenzyl chloroformate, p-rol chloroformate, and benzyl chloroformate. These BYCFs are usually obtained by reacting the corresponding benzyl alcohol with phosgene in an organic solvent such as tetranohydrofuran, toluene, methylene chloride or in the absence of a solvent at a temperature range of -20 to 10°C. be able to. On the other hand, ATD is a commonly available commercially available product, and examples of the mineral salt include hydrochloride, phosphate, and sulfate. If the amount of BYOF used is too large, the excess BYCF will decompose and it will be difficult to obtain the desired 0BZ-AA with high purity.
Usually 0.0 for ATD. A range of q to 0 mol times, preferably 0.5 to 0 q mol times can be mentioned.

The caustic alkali to be present is usually caustic soda or caustic potash, and the amount used is, for example, ATD
A range of 7.3 to 2.0 times the amount by mole can be mentioned.

The organic solvent used in the present invention may be any solvent as long as it is inert to the reaction and can dissolve the raw material BYCF, such as aliphatic chlorinated hydrocarbons such as methylene dichloride, ethylene dichloride, carbon tetrachloride, and chloroform; Examples include aromatic chlorinated hydrocarbons such as chlorobenzene, dichlorobenzene, and trichlorobenzene, aromatic hydrocarbons such as benzene, toluene, and xylene, and ethers such as diethyl ether, diisopropyl ether, dibutyl ether, and tetrahydrofuran.

The amount of organic solvent used should be at least
Although the amount to dissolve F is necessary, an excess amount is usually used in order to make the reaction progress well, and is selected, for example, from a range of /-10 times the weight of BYCF. In addition, the amount of water used, which is the other solvent component, is at least
An amount is required to dissolve TD and caustic, and usually,
It is selected from the range of / to 5 times the weight of ATD.

The reaction temperature of the present invention is usually in the range of -20 to 20°C, preferably -10 to 10°C; if this temperature is too low, it will require a large amount of equipment and energy for cooling, making it uneconomical; If the temperature is high, the decomposition of BYOF will increase, resulting in a high yield of C! In addition to not being able to obtain BZ-AA,
This is not preferable because ATD decomposes. Since the reaction of the present invention is exothermic, typically BYC! It is preferable to control the feed rate of F and caustic alkali, to carry out the reaction while cooling the system, and to maintain the temperature within the above range throughout the entire reaction period.

Further, the reaction time is usually about 1 to 20 hours, and since the reaction of the present invention proceeds simultaneously with the dropping of BYOF and caustic alkali, substantially all of the reaction time is the time for supplying BYCF and caustic alkali. BYOF and caustic feed may be provided intermittently, but are normally continuous.

In the present invention, when BYOF and ATD are reacted, A
An aqueous solution of TD and caustic alkali is used as a bedding liquid, and BYC is added to this.
It is an essential requirement that the reaction be carried out by gradually supplying F. With this reaction method, high purity C! BZ-AA can be obtained in a high yield. However, for example, when BYCF is used as a base liquid, the effects of the present invention cannot be obtained.

In the reaction of the present invention, it is usually preferable to maintain the pH within the system in a range of 71 or higher, preferably 12 or higher. In the reaction of the present invention, the pH within the system decreases as the reaction progresses, but it is preferable to adjust the amount of caustic alkali used so that the pH is maintained at 12 or higher at the end of the reaction.

Further, in the present invention, it is preferable that a part of the organic solvent be present as a bedding solution, if necessary, because the reaction proceeds smoothly. In this case, the amount of organic solvent present as a bedding solution is usually 10 times the weight of the bedding solution.

(Effects) According to the present invention, the selectivity of the target compound CBZ-AA can be increased, and as a result, a highly purified product can be obtained at a high yield.The present invention has such excellent effects. Although the cause of this phenomenon is unknown, the industrial value of the present invention is great because the selection of a simple reaction method can make a difference.

(Examples) Next, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited to the following Examples.

Example 1 An aqueous solution of ATD (hydrochloride)/ll-Lu1l (/, S mol) dissolved in water/lIgl, 25% caustic soda aqueous solution II 00 g was placed in a 3t glass reactor equipped with a stirrer set to a temperature controller. (2.3 mol as NaOH) and methylene dichloride/30011 were added, and while maintaining the liquid temperature at -3 to θ°C, p-nitropenzyl alcohol roformate u/j, Ag (7.0 mol) was added. A solution prepared by dissolving 30 y of methylene dichloride was gradually added dropwise over 2 hours, and then the reaction was carried out by holding at the same temperature for 30 minutes.

After the reaction, the mixture was filtered at 0°C to separate the precipitated p-nitrocarbobendiyloxyacetamidine crystals, which were washed sequentially with 300,011 water and 22,011 methylene dichloride. , under reduced pressure, II
Drying treatment was carried out at 0° C. for 2 hours.

The purity of the thus recovered p-nitrocarbobendiyloxyacetamidine/crystals and the yield of p-nitropenzyl chloroformate were determined, and the The selectivity was determined and the results shown in Table 1 were obtained.0 Comparative Example 1 In the method of Example/2, components other than the 2-tack caustic soda aqueous solution were charged in advance into the reactor, and the liquid temperature was maintained at -3 to θ°C. In the same manner as in Example 1, the same amount of 45% caustic soda aqueous solution was gradually added dropwise over an hour.
Table 1 shows the results when the reaction was carried out.

In the method of Example 1 in Table 1, the reaction scale is 4, and p-
For nitrobenzyl chloroformate, benzyl chloroformate g J...? , 9 (O, S mol), a solution of this dissolved in methylene dichloride was gradually added dropwise over a period of time, and the same reaction as in Example 1 was carried out to obtain υcarbobendiyloxyacetate. Amidine was produced.

The mixture obtained in this reaction was separated into an aqueous phase and an oil phase, and the oil phase was analyzed by high performance liquid chromatography to determine the selectivity and yield of carbobendiyloxyacetamidi/, which are shown in Table 2. Got the results.

Comparative Example 2 In the method of Example 2, components other than the 2S% aqueous solution were charged in advance into a reactor, and while maintaining the liquid temperature at -3 to θ°C,
Table 2 shows the results when the reaction was carried out in the same manner as in Example 1 by gradually dropping the same amount of aqueous sodium hydroxide solution over 2 hours.

Table 2 Sender: Mitsubishi Chemical Industries, Ltd. Representative Patent Attorney Hase - (7 others)

Claims (3)

[Claims] (1) In a method for producing carbobendiyloxyacetamidines by reacting benzyl chloroformates and acetamidine mineral salts in the presence of a caustic alkali in a water-organic solvent, the method comprises: and carbobendiyloxyacetamidine, which is characterized in that the reaction is carried out with an aqueous solution of a caustic alkali and, if necessary, an organic solvent as a bedding solution, while gradually supplying a benzyl chloroformate or its organic solvent solution. kind of manufacturing method. (2) Carbobendiyloxyacetamidines according to claim (1), characterized in that the amount of caustic alkali used is 1.3 to 2 times the mole of the acetamidine mineral salt. manufacturing method. (3) A method for producing carbobendiyloxyacetamidines according to claim (1), characterized in that the reaction temperature is maintained in the range of -20 to 10°C.