JPS629589B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a process for producing ortho- and para-hydroxybenzyl cyanides in which the corresponding ortho- and para-hydroxybenzyl alcohols are optionally substituted in the aromatic nucleus. Due to the effect of activation of the phenolic group, ortho- and para-hydroxybenzyl alcohols can be halokenated in a suitable solvent and then reacted with sodium cyanide to form the corresponding benzyl alcohols in practical yields. It is well known that it cannot be converted to cyanide. However, in the case of ortho- and para-hydroxybenzyl alcohols, it is possible to achieve the desired conversion under manufacturing conditions that do not involve the use of acidic reagents. For example, para-hydroxybenzyl alcohol
Using a 4% solution of the starting material in dimethylformamide, this was heated with sodium cyanide at 110°C to 130°C.
By heating for 20 hours at a temperature range of 67 °C
(Schwarz et al., J.Org.Chem.1976, 41 2502~
3). Additionally, para-hydroxybenzyl alcohol is first converted to the corresponding diacetate with acetic anhydride and then this diacetate is reacted with potassium cyanide in methanol solution to obtain the product with a yield of 70%. (Hayashi et al., Bull.Inst.Chem.Res., Kyoto Univ.1974, 52
514). However, these reactions have the disadvantage that in the former case a large excess of expensive solvent is used and in the latter case the corresponding diacetate must be prepared using expensive reagents. It is clearly desirable in general to provide synthetic methods that are more advantageous than previously known methods. The conditions are, for example, that the reaction can be carried out under mild conditions, that relatively inexpensive and easily obtained reagents and solvents can be used, that the yield is good, that the separation method is simple, and that there is no need to separate intermediates. There is no such thing. A method suitable for obtaining such advantages has not yet been discovered. The present invention therefore provides a process for the preparation of ortho- or para-hydroxybenzyl cyanide, which comprises the reaction of ortho- or para-hydroxybenzyl alcohol with cyanide and an ester capable of esterifying benzyl hydroxyl groups. . The esters used in the invention are typically aliphatic esters of primary alcohols. Esters suitable for use in the process of the invention are acetic acid esters and formic acid esters. Surprisingly, it has been found that the use of formic acid esters often has considerable advantages over the use of acetic acid esters. For example, when formic acid ester is used, the yield is high. Particularly preferred esters are methyl formate and ethyl formate. Cyanides suitable for use in the process of the invention are alkali metal cyanides. It is believed that these cyanides inherently facilitate the reaction. Preferred cyanides for use in the present invention are sodium or potassium cyanides. The process of the invention is carried out in a suitable organic solvent.
It is particularly advantageous if the solvent is a primary alcohol. The most suitable solvents for the process of the invention are methanol and ethanol. The reaction is generally carried out at elevated temperatures, most suitably under reflux. The reaction is preferably carried out by mixing the reactants in a solvent and stirring while keeping the reactants at a high temperature. A temperature at which the mixture refluxes is suitable. It is believed that under the reaction conditions, the ortho- and para-hydroxybenzyl alcohols are sequentially esterified with a base-containing esterification agent, and the ester in the solvent-mediated reaction mixture is catalytically alcoholyzed. Alkali metal cyanides are used as base catalysts. The following reaction diagram shows the reaction process of para-hydroxybenzyl alcohol in the presence of a cyanide such as sodium cyanide and a formic acid ester such as methyl formate in a solvent such as methanol. Diesters () and monoesters by reaction A mixture of () and () is created. The formation of reactive quinone methides () is possible only in the case of monoesters () with the function of free phenols, which can be converted to the desired formation by addition of cyanide by base catalysis. You can create things. This reaction system has the advantage that unreactive esters () and () are converted to reactive esters () based on the equilibrium relationship of the system. The ester () is removed from the system by an irreversible reaction to give the compounds () and (), and the unreactive ester is gradually converted to the reactive ester, thereby increasing the yield of the desired product. increase advantageously. Particular preference is given to using formic acid esters in the reaction. In view of the above, from another aspect, the present invention also provides a process for producing ortho- or para-hydroxybenzyl cyanide by reacting ortho- or para-hydroxybenzyl formate with sodium or potassium cyanide. It is clear that this is what they are offering. This type of process of the invention is preferably carried out by using primary alcohols as solvents.
Preferred primary alcohols for use in the present invention are methanol or ethanol. Generally, this type of process of the invention is carried out at elevated temperatures and most preferably under reflux. The formic acid ester used in this case may be prepared in advance, but it is best to prepare it on-site by transesterification of hydroxybenzylphenol with a formic acid ester such as methyl formate or ethyl formate. The process of the invention is typically carried out in a medium consisting of a mixture of primary alcohol and aliphatic ester. The ratio of primary alcohol to aliphatic ester in the reaction medium is governed to some extent by the rate of reaction. When the ratio of primary alcohol to aliphatic ester is low or high, the reaction rate is too slow, resulting in the formation of undesired by-products. A suitable ratio of alcohol to ester is 1:1 to 4:1 by volume. A preferred mixture contains from 2 to 4 parts alcohol to 1 part ester by volume. Preferably, the ester used as the reaction medium is formic acid ester, and the primary alcohol is methanol or ethanol. It is clearly a considerable advantage that the process of the present invention can use readily available and relatively inexpensive materials such as methanol, ethanol, methyl formate and ethyl formate. After the reaction of the present invention is complete, the solvent and remaining unreacted reactants can be recovered from the reaction mixture. Suitably, this recovery is by distillation. The reaction products and unreacted starting materials are separated from the inorganic salts by acidification with a dilute mineral acid such as sulfuric acid, and the organic materials can be extracted by partition into an organic solvent.
Suitable organic solvents are methylene chloride and chloroform. The various organic extracts are processed as follows. The organic solvent is first removed by evaporation and then the pure product in the process of the invention is separated by vacuum distillation. As will be understood by advanced chemists, the process of the present invention is also applicable to ortho- or para-hydroxybenzyl alcohols having substituents on the aromatic nucleus (excluding, of course, those that would hinder the reaction). Suitable substituents are lower alkoxy groups such as methoxy groups. This type of hydroxybenzyl alcohol includes vanillyl alcohol. The following examples illustrate the invention. Example 1 Preparation of para-hydroxybenzyl cyanide compound. Para-hydroxybenzyl alcohol 4.96g,
A mixture of 2.8 g of sodium cyanide, 18 ml of methanol and 6 ml of methyl formate was heated under reflux with stirring for 70 minutes. The reaction mixture was distilled under reduced pressure to recover the starting material, 20 ml of water was added to the residue and sulfuric acid was added with stirring until the mixture was no longer alkaline. The product was then separated by repeating the extraction three times, each time using 15 ml of methylene chloride. The various solvent extracts were washed with 10 ml of aqueous sodium bicarbonate solution and the solvent was removed by vacuum distillation at a temperature of about 60°C. 5.11 g of crude para-hydroxybenzyl cyanide was obtained. The yield corresponds to 96% of theory by weight. Simply distilling in an oil pump vacuum gives a pale yellow component with a melting point of 65°C, corresponding to a yield of 93% of theory by weight.
Melting point values indicate that the material is 97% absolute pure. Example 2 Production of para-hydroxybenzyl cyanide Para-hydroxybenzyl alcohol 4.96
g, sodium cyanide 2.4g, ethanol 12ml
and ethyl formate (12 ml) was heated under reflux for 90 minutes with stirring. The reaction product was separated as in Example 1 to obtain a crude product with a yield of 94% and a melting point of 58-61°C (uncorrected). Example 3 Production of para-hydroxybenzyl cyanide The reaction was carried out in the same manner as in Example 1 except that methyl acetate was used instead of methyl formate. Para-hydroxybenzyl cyanide was obtained, the yield of which was inferior to that in Example 1. Example 4 Production of ortho-hydroxybenzyl cyanide The reaction was carried out in the same manner as in Example 1, except that ortho-hydroxybenzyl alcohol was used instead of para-hydroxybenzyl alcohol.
Ortho-hydroxybenzyl cyanide (crude product) was obtained with a yield of 92.7%. Example 5 Production of 4-hydroxy-3-methoxybenzylane compound The reaction was carried out in the same manner as in Example 1 except that 4-hydroxy-3-methoxybenzyl alcohol was used instead of para-hydroxybenzyl alcohol. 4-hydroxy-3 in 77.4% yield
-Methoxybenzyl cyanide (crude product) was obtained.

Claims (1)

[Scope of Claims] 1. An aromatic alcohol selected from ortho- and para-hydroxybenzyl alcohol is mixed with a cyanating reagent and an ester capable of esterifying the aromatic alcohol in methanol and/or ethanol as a solvent. Let it react,
A method for producing an aromatic cyanide selected from ortho- and para-hydroxybenzyl cyanides, characterized in that an aromatic cyanide is obtained. 2. The method according to claim 1, wherein the cyanating reagent is selected from sodium cyanide and potassium cyanide. 3. The method according to claim 1 or 2, wherein the ester is a fatty acid ester of a primary alcohol. 4. The method according to claim 1 or 2, wherein the ester is a formic acid ester. 5. The method according to claim 4, wherein the formic acid ester is selected from methyl formate and ethyl formate. 6. A method according to any of the preceding claims, wherein the reaction is carried out at an elevated temperature. 7. A process according to any of the preceding claims, characterized in that the reaction is carried out under reflux. 8 The ratio of methanol and/or ethanol to ester is about 1:1 to about 4:1 by volume.
A method according to any of the preceding claims, comprising: 9. The cyanating reagent is sodium cyanide or potassium cyanide, the aromatic alcohol is ortho- or para-hydroxybenzyl alcohol, and the ester is formate, the ratio of alcohol to ester being about 2:1 to 4 by volume. 2. A process according to claim 1, wherein the reaction is carried out at about reflux temperature under :1. 10 An aromatic ester selected from ortho- and para-hydroxybenzyl formate,
selected from ortho- and para-hydroxybenzyl cyanides, characterized in that they are reacted with cyanides selected from sodium cyanide and potassium cyanide in methanol and/or ethanol as solvent to obtain aromatic cyanides. A method for producing aromatic cyanide. 11. The method according to claim 10, characterized in that the reaction is carried out under reflux. 12 Claim 10 wherein the ratio of methanol and/or ethanol to ester is from about 1:1 to about 4:1 by volume.
or the method according to paragraph 11. 13. The process of claim 10, wherein the reaction is carried out at about reflux temperature in a ratio of alcohol to ester of about 2:1 to 4:1 by volume. 14 Aromatic alcohol selected from ortho- and para-hydroxybenzyl alcohol,
Reacting a cyanating reagent selected from sodium cyanide and potassium cyanide and a formic acid ester in methanol and/or ethanol as a solvent at about reflux temperature under an alcohol to ester ratio of 2:1 to 4:1 by volume. After the reaction, the excess solvent and unreacted reactants are recovered by distillation, and after distillation, the aromatic cyanide is separated from the inorganic salt by extraction from the acidic aqueous medium into an organic solvent, and the organic solvent is evaporated. 1. A method for producing an aromatic cyanide selected from ortho- and para-hydroxybenzyl cyanides, which comprises distilling the aromatic cyanide under reduced pressure to obtain pure aromatic cyanide. 15 An aromatic ester selected from ortho- and para-hydroxybenzyl formates is mixed with a cyanating reagent selected from sodium cyanide and potassium cyanide in methanol and/or ethanol as a solvent, adjusting the ratio of alcohol to ester by volume. About 2:1 to 4:
1 at approximately reflux temperature, excess solvent and unreacted reactants after the reaction are recovered by distillation, and after distillation, the aromatic cyanide is extracted from the acidic aqueous medium into an organic solvent to form an inorganic Aromatic selected from ortho- and para-hydroxybenzyl cyanide, characterized in that the aromatic cyanide after separation from the salt and evaporation of the organic solvent is distilled under reduced pressure to obtain pure aromatic cyanide. Method for producing group cyanides.