JPS5855442A - Synthesizing method of p-hydroxybenzaldehyde - Google Patents

Abstract

PURPOSE:To obtain p-hydroxybenzaldehyde useful as anticancer agent, etc. in high yield and selectivity, by reacting phenol with cyclodextrin and chloroform in a specific molar ratio in the presence of NaOH, etc. CONSTITUTION:Cyclodextrin is dissolved in an aqueous solution of a phenol and NaOH or KOH, and chloroform is added thereto to keep >=0.5mol ratio between the cyclodextrin and the chloroform present in the reaction system. The reaction is then carried out at 30-80 deg.C to give the aimed compound in almost 100% selectivity. Either one of the alpha- or beta-cyclodextrin may be used as the cyclodextrin, and the amount thereof to be added is preferably 0.01-0.20mol equivalent based on the charged phenol. The cyclodextrin can be recovered and reused completely without changing in the reaction. USE:A raw material for medicines, agricultural chemicals, dyes, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a process for the synthesis of parahydroxybenzaldehyde.

Rosehydroquine benzaldehyde is used as an anticancer drug.
Its importance has recently increased as a raw material for medicines, agricultural chemicals, dyes, etc.

Conventionally, a method for synthesizing hydroxybenzaldehyde by reacting phenol and chloroform in the presence of an alkali has been known.

However, as seen in Comparative Example 1 below.

The selectivity for producing parahydroxybenzaldehyde in this reaction is about 30%, and a large amount of salicylaldehyde is produced as a by-product. Therefore, obtaining parahydroxybenzaldehyde by this method required a large amount of raw materials and one separation operation.

Also, Pharmazie magazine, Volume 33, 1978
Published in 2016.

On page 467, it is reported that when β-cyclodextrin is added to the above reaction system, the selectivity for producing parahydroxybenzaldehyde is improved. However, since the entire amount of raw material chloroform was added by the usual method at the start of the second reaction, it was necessary to add 0.75 molar equivalent of β-cyclodextrin to the charged phenol to obtain a selectivity of 95% at a conversion rate of 19%. Requires addition.

Recently, the present inventors discovered that the molar ratio of cyclodextrin and chloroform present in the reaction system has a significant effect on this selectivity, and as a result of intensive research, they found that Added cyclodextrin to an aqueous solution of potassium hydroxide, dissolved it, and then added chloroform to keep the molar ratio of cyclodextrin and chloroform present in the reaction system at 0.5 or higher to produce parahydroxybenzaldehyde in high yield. rate,
We succeeded in synthesizing it with high selectivity. Examples 1 and 2
As shown in Figure 1, the selectivity of parahydroxybenzaldehyde, which is the object of the present invention, is approximately 100%.

As the cyclodextrin, both α-cyclodextride and β-cyclodextrin can be used.

The amount of cyclodextrin added in the present invention is 0.00001 to 0.50 molar equivalent, preferably 0.01 to 0.20 molar equivalent, per one charged phenol.

By adding such a small amount of cyclodextrin, the desired product can be produced with nearly 100% selectivity.

On the other hand, according to the conventional method in which the entire amount of raw material chloroform is added at the start of the second reaction, 0.0
The selectivity of the target product when 1 to 0.05 molar equivalents of siphrobuchistrin was added was 30 to 35%, and no significant difference was observed from the value when no cyclodextrin was added (33%).

According to the conventional method, as seen in Comparative Examples 2 and 3.

Even if 0.20 molar equivalents of 7 clodextrin were added to the charged phenol, the selectivity of the target product was 45 to 60%.
It remains to a certain extent. From this, it is clear that the manufacturing method according to the present invention is superior.

The concentration of the aqueous solution of sodium hydroxide or potassium hydroxide in the present invention is 0.1 to 50% by weight, preferably 5 to 20%. Also, the temperature of one reaction is 30 to 12
0''O, preferably 50-80°C.

For example, batch reactors and flow reactors can be used in the practice of the present invention.

Cyclodextrin does not change during the reaction, and when the reaction system is made acidic after 5 reactions, cyclodextrin precipitates due to a decrease in solubility. This easy way to kiss shifrobuki) I
More than 80% of J is recovered, and the recovered cyclodextrin can be completely reused.

Next, the present invention will be specifically explained with reference to Examples, but the present invention is not limited thereto.

Example 1 α-Cyclodextrin (manufactured by Hani Ihigaku Pharmaceutical Co., Ltd.,
A special grade reagent) was dissolved in 50 ml of an aqueous solution of 1 fuum of 10 thihydroxide, and the reaction solution was heated to 60° C. while stirring using a magnetic force and a stirrer. While 3 ml (37 mmol) of chloroform (manufactured by Tokyo Ihi Seiko Co., Ltd., special grade reagent) was added dropwise, the reaction was allowed to proceed for 10 hours. The reaction solution was separated every 2 hours, and the amount of chloroform in it was measured using a gas chromatograph model 701 manufactured by Okura Institute of Science and Technology Co., Ltd. , 2 m; Zolam temperature, 30° C.; carrier gas, helium) As a result of analysis, the ratio of α-7 clodextrin and chloroform was 0.9 to 1.6. After the reaction, add hydrochloric acid to the 2-reaction liquid to make it acidic + 50
ff7? Extracted 5 times with ethyl/leair. The ether layer was washed with water and evaporated to dryness in a jar to obtain 1.1y of solid. This solid was treated with benzene to obtain a 0.6y Hensen insoluble part and a 0.5y benzene soluble part. The infrared absorption spectrum of the benzene-insoluble portion coincided with the spectrum of S-hydroxybenzaldehyde (manufactured by Tokyo Kasei Kogyo Co., Ltd., special grade test cauterization), and the spectrum of the benzene-soluble portion was identical to the spectrum of phenol.

1 inch/L for benzene soluble and benzene insoluble parts.

1 I couldn't watch aldehyde. That is, the selectivity of the target product was 100%, and the yield considering unreacted phenol was 92 mol.

The amount of β-cyclodextrin used in this example is 0.2 molar equivalent relative to phenol.

7 Example 2 In place of α-7 clodextrin 2 and 21 in Example 1, 2.4y (2.1 mmol) of β-cyclodextrin (manufactured by Hanui Chemical Co., Ltd., special T-class reagent) was used. The same operation as in Example 1 was carried out except for the use of the following. As a result, o,5y (4.0 mmol) of parahydroquine benzaldehyde was obtained, and 0.6y of unreacted phenol was recovered. Salicylaldehyde was not detected. In other words, the selection rate of the target object is 100%,
The yield, taking into account unreacted tuonol, was 96 mol.

The amount of β-cyclodextrin used in this example was 0.2 molar equivalent based on the charged phenol.

Comparative example 1 1.01! (10.6 mmol) of phenol (manufactured by Koso Chemical Co., Ltd., - grade reagent) was dissolved in 50 ml of 10% sodium hydroxide aqueous solution.9 The reaction solution was stirred using a magnetic stirrer and heated to 60°C. did. While 3 mA' (374 mmol) of chloroform (manufactured by Tokyo Chemical Industry Co., Ltd., special grade reagent) was added dropwise thereto, the reaction was allowed to proceed for 10 hours. After the reaction, add hydrochloric acid to the reaction solution to make it acidic.
Extracted 5 times with 50me ethyl ether. The ether layer was washed with water and then evaporated to give 1.0y of oil. Gas chromatograph type 701, manufactured by Oshoku Rikagaku Kenkyusho Co., Ltd. (filling material, manufactured by Gascro Industries Co., Ltd., Uniboat HP; column length: 2 m; column temperature, 140°C)
As a result of analysis with carrier gas helium), this substance was found to contain 0.2y (1.6 mmol) of parahydroxybenzaldehyde, 0.4F (3.2 mmol)
of salicylaldehyde, and 0.4y of phenol. That is, the selectivity of the target product was 33 moles, and the yield considering unreacted thunol was 26 moles.

In this example, the usage amount of Schiflovkis l-IJ is 0.

Comparative Example 2 1.OF (10.6 mmol) of phenol (manufactured by Koso Chemical Co., Ltd., − grade reagent) and 2.2y (2.1
1 mmol) of α-cyclodextrin (manufactured by Hanui Chemical Co., Ltd., special grade reagent) was dissolved in 50 ml of 10% sodium hydroxide aqueous solution, and 3meC3''14 mmol) of chloroform (manufactured by Tokyo Kasei Kogyo Co., Ltd., special grade reagent) was dissolved in 50 ml of 10% sodium hydroxide aqueous solution. That is, the molar ratio of α-cyclodextrin and chloroform at the start of the second reaction was 0.06.The reaction solution was stirred using a magnetic stirrer and heated at 60'O for 10 hours. After the reaction, add hydrochloric acid to the reaction solution to make it acidic, and add 50ml of ethyl ether to
Extracted twice. The ether layer was washed with water and then evaporated to give 1.1y oil. Gas chromatograph type 701 manufactured by Oshoku Rikagaku Kenkyusho Co., Ltd. (filling material, Unibo manufactured by Gascro Industries Co., Ltd.) HP; - Column length.

2m; column temperature, 140"O, carrier gas.

As a result of analysis with helium), this substance was found to be 0.4y (3
, 2 mmol) noharahydroxybenzaldehyde,
It was a mixture of 0.3y (2.4 mmol) salicylaldehyde and 0.4y phenol. In other words, the selection rate of the target object is 57.

The yield, taking into account unreacted phenol, was 51 mol.

The amount of α-cyclodextrin used in this example was 0.2 molar equivalent relative to the charged phenol, which was the same as in Example 1.

Comparative Example 3 Comparison except that 2.4y (2.1 mmol) β-cyclodextrin (manufactured by Hanui Chemical Co., Ltd., special grade reagent) was used instead of 2,2y α-cyclodextrin in Comparative Example 2. The same operation as in Example 2 was performed. That is, the molar ratio of β-cyclodextrin and chloroform at the start of the second reaction was 0.06. As a result, 0
．． 3! (2,4S IJ mol) Noparahydride 7 Benzaldehyde (!: 0.2 F (1,6 mmol)
of salicylaldehyde and 0.5y of thunol was obtained. Namely.

The selectivity of the target product was 60%, and the yield considering unreacted tunaol was 46 mol.

The amount of β-cyclodextyl IJ used in this example was 0.2 molar equivalent based on the charged tunol, which was the same as in Example 2.

Patent applicant Hidefumi Hirai

Claims (1)

[Claims] When phenol and chloroform are reacted in the presence of sodium hydroxide or potassium hydroxide, the molar ratio of cyclodextrin and chloroform in the reaction system is maintained at 0.5 or more. A method for highly selectively producing parahydroxybenzaldehyde using 0.5 molar equivalent or less of cyclodextrin relative to the charged phenol.