PROCESS FOR THE PREPARATION OF ALPHA-HYDROXYCARBOXYLIC ACID AMIDES

Abstract: The invention relates to a process for the preparation of α-hydroxycarboxylic acid amides of the formula: where R₁ represents alkyl, alkaryl, aryl, alkenyl, heteroalkyl or heteroaryl, whether or not substituted, R₂ represents hydrogen or methyl, or R₁ and R₂ together form cycloalkyl, by conversion of the corresponding cyanohydrins, and is char­ acterized in that the conversion takes place in the presence of hydrogen peroxide and ammonia. By preference use is made of 2-6 moles hydrogen per­ oxide and 0.5-3 moles ammonia per mole cyanohydrin.

Description: PROCESS FOR THE PREPARATION OF a-HYDROXYCARBOXYLIC ACID AMIDES The invention relates to a process for the preparation of a-hydroxycarboxylic acid amides of the formula: EMI1.1 where R1 represents alkyl, alkaryl, aryl, alkenyl, heteroalkyl or heteroaryl, whether or not substituted, R2 represents hydrogen or methyl, or R1 and R2 together form cycloalkyl, by conversion of the corresponding cyanohydrins The a-hydroxycarboxylic acid amides obtained can be applied as intermediary in the preparation of optically active a-hydroxy acids. Both the amides and the acids can be applied in the pharmaceutical, the agricultural and the flavours and fragrances industries. From Eliel, E.L. and Freeman, J.P., Organic Synthesis CoIl. Vol. IV (1963), pp; 58-62, it is known to prepare a-methyl,x-hydroxy- carboxylic acid amides by hydrolysis of the cyano group of a corresponding cyanohydrin using concentrated HCl during a reaction that takes 18 hours, after which the reaction mixture is cautiously neutralized. The drawback of such a process resides in the corrosive properties of concentrated HCL, the long reaction time, the formation of hydrocyanic acid in the mixture and the release of much inorganic salt during the neutralization reaction. Salt-free working is necessary notably if the amide obtained is converted into the L-acid and the D-amide using enzymatic methods, the reaction rate of an enzymatic conversion being adversely affected by high salt concentrations. The object of the invention is elimination of the drawbacks referred to. The invention therefore provides a process for the preparation of a-hydroxycarboxytic acid amides of the formula EMI2.1 where R1 represents alkyL, atkaryt, aryL, atkenyl, heteroalkyl or heteroaryt, whether or not substituted, R2 represents hydrogen or methyl, or R1 and R2 together form cycloalkyt, by conversion of the corresponding cyanohydrins and is characterized in that the conversion takes place in the presence of hydrogen peroxide and ammonia. Thus it is achieved that a-hydroxycarboxylic acid amides, a -hydroxya -raethytcarboxy Li c acid ami des and a -hydroxy-a -cyctoa1ky I- carboxytic acid amides can be prepared in a simpLe and economically sound manner. Another advantgae is that the &alpha;-hydroxycarboxylic acid amides obtained can simpLe be converted into the corresponding a-hydroxy acids using 1 to 2 equivatents of a strong base such as NaOH or KOH. It is true that an a-hydroxy acid can be prepared directly from the corresponding a-hydroxynitrite, but this is possible only if use is made of 6 equivatents of a strong acid such as HCt. The drawback then again is the highLy corrosive environment. It cannot but be called surprising that the nitrile group should be converted selectively in the process according to the invention, for from Tanaka, M. et at., Angew. Chew. (1984) 2µ pp. 519-520, it is known that in the presence of t-butyl hydroxyperoxide and a ruthenium catalyst various cyanohydrins are converted into the corresponding ketones, that is into 2-oxoalkane nitriles. The process according to the invention is preferably carried out in the presence of 2-6 motes hydrogen peroxide, in particular in the presence of about 2.2 moles hydrogen peroxide, per mote cyanohydrin. It is generally attempted not to use more moles hydrogen peroxide per mole cyanohydrin than is strictLy necessary. The amount of ammonia to be applied in the process according to the invention may vary between 0.5 and 3 motes NH3 per mole cyanohydrin. In particular use is made of less than 2 moles NH3. Use of more than 3 moles NH3 may effect the conversion of hydroxy nitrile into amino nitrile; any conversion into amino nitrile, however, is dependent on the stability of the corresponding hydroxy nitrite. This stability determines the maximum allowable concentration of ammonia if a pure reaction product is desired. Upon termination of the reaction the excess hydrogen peroxide can be reduced using, for instance, palladium-on-carbon, after which the excess ammonia can be removed by, for instance, distillation. In this way the formation of salts, besides the desired a-hydroxycarboxylic acid amides, that subsequently need to be removed, is prevented. The basic environment present during the reaction also prevents the release of the extremely toxic hydrocyanic acid. The process according to the invention can be carried out at various temperatures. By preference a temperature between n and 50nC is aoplied, in particular between 25 and 40no. As the cyanohydrins are thermally unstable, the reaction temperature is preferably kept low. The stability of the a-hydroxy nitrile determines the allowable temperature. The cyanohydrins decompose notable above 60nC into cyanide and ketones, upon which the cyanide may polymerize under the reaction conditions then prevailing. The process is generally carried out in solvents such as water and lower alcohols, such as methanol, ethanol, propanol, isopropanol, butanol, etc. Higher alcohols can in principle also be used, but are less interesting because of the poorer compatibility with water. Furthermore other organic solvents that can be mixed with water can be used, such as dioxane and tetrahydrofuran. In this way the reaction is completed within a few hours, irrespective of whether R2 is hydrogen or methyl, or whether R1 and R2 together form a cycloalkyl. The reaction is not affected by R1, either, which may therefore in principle be chosen at random. R1 will generally be an alkyl, aryl, alkaryl, alkenyl, heteroalkyl or heteroaryl group, it of course being possible for the alkyl group to be cyclic. The bulkiness of this group is not important, either, but R1 will mostly not contain more than 20 carbon atoms. OptionalLy RI may be a substituted hydrocarbon residue, insofar as the substituent does not react under the reaction conditions. As such, notably oxygen and nitrogen containinq compounds can be mentioned, in particular alkoxy and alkyl amine. R2 may also form a cycloalkyl together with R1. The optically active &alpha;-hydroxycarboxylic acid amides and corresponding acids will generally find application as intermediaries for the agricultural, the pharmaceutical and the flavours and fragrances industries. R1 thus preferably is an organic group, whether or not substituted, that is closely related to corresponding groups of natural hydroxy acids. Examples are methyl, ethyl, isopropyl, 2-butyt, benzyt, methoxy-substituted benzyl groups, hydroxymethyL and methoxymethyl. The a-hydroxy nitrites can, for instance, be synthesized by addition of hydrocyanic acid to ketones or atdehydes. A process for this is described, for instance, in US-A-2,745,865. The conversion of the nitrite into the amde may take place immediately upon addition. It is not necessary, and often even undesirable, to isolate the cyanohydrin, as these compounds may be thermalty unstable. After the conversion into &alpha;-hydroxycarboxylic acid amides, which are stable at the usual temperatures, first the excess hydrogen peroxide can be decomposed using a reducing agent, following which the excess ammonia can simply be evaporated. Subsequently, if desired separation of the optical isomers may take place. The Ls°-hydroxy acid can be obtained by optical separation of the D,L-compound, for instance by application of an amidase-containing enzyme preparation obtained from a culture of Rhodococcus erythroootis. The optical separation of the D,L-compounds could, however, also be effected using physicochemical methods, in which the virtually pure racemic mixture can very simply be used as starting material. Thea-hydroxyamethylcarboxylic acid amides and corresponding acids, a-hydroxya-hydrogencarboxyic acid amides and corresponding acids and &alpha;-hydroxy-&alpha;-cycloalkylcarboxylic acid amides and corresponding acids can serve as intermediaries in the synthesis of products for the agricultural, the pharmaceutical, and the flavours and fragrances industries. By way of example of their aoplications mention may be made of D-2-hydroxy-3-(3,4-dihydroxyphenyl)-propionic acid in 'Rosmarinic acid' which can be used as antioxidant and in fighting inflammations. The invention will be elucidated with reference to the following examples, without being restricted thereto. Example I An amount of 33 g of the hydroxy nitrile of benzaldehyde was added in about 1 hour to a solution of 25 ml concentrated ammonia and 60 ml hydrogen peroxide (30X) in 250 ml water. The temperature of the reaction mixture was kept below 40nC by cooling. After 3 hours' stirring the hydrogen peroxide was reduced using 1 g palladium-oncarbon and the palladium-on-carbon was filtered off. The aqueous layer was subsequently evaporated at reduced pressure (T c 40nC) and a crystalline a-hydroxybenzylcarboxylic acid amide remained. After washing with 100 ml toluene the yield was 32,0 g (85X). Examples Il-Vi As the a-hydroxy nitriles listed in Table 1 are thermally unstable, they preferably are used immediately after the synthesis, without further isolation. The addition of cyanic acid to an aldehyde or ketone using an acid catalyst is effected in an aqueous medium, with a yield of 50-80%, the a-hydroxynitrile being separable in an organic phase. After the preparation of a-hydroxy nitriles, starting from aldehydes and ketones (Table 1), each-a-hydroxycarboxylic acid amide was prepared in the same manner as in Example 1. The products obtained, and the yields, starting from the aldehyde or the ketone (the overall yield of both nitrile preparation and amide preparation according to the invention) are also shown in Table 1. Table 1 ExampLe aldehyde or ketone a-hydroxycarboxylic acid amide yield R1 R2 II phenylpropionaldehyde C6H5CH2CH2- H- 65% III isobutyraldehyde (CH3)2 CH- H- 60% IV acetone -CH3 -CH3 75% V cyctohexanone -CH2-CH2-CH2- -CH2-CH2- 70X VI methytethylketone CH3-CH2- -CH3 50X

Claims: CLAIMS 1. Process for the preparation of a-hydroxycarboxylic acid amides of the formula: EMI7.1 where R1 represents alkyl, alkyl, aryl, alkenyl, heteroalkyl or heteroaryl, whether or not substituted, R2 represents hydrogen or methyl, or R1 and R2 together form cycloalkyl, by conversion of the corresponding cyanohydrins, characterized in that the conver sion takes place in the presence of hydrogen peroxide and ammonia. 2. Process according to claim 1, characterized in that It is carried out using 2-6 moles hydrogen peroxide per mote cyanohydrin. 3. Process according to claim 2, characterized In that use is made of about 2.2 moles hydrogen peroxide per mole cyanohydrin. 4. Process according to any of claims 1-3, characterized in that it is carried out using 0.5-3 moles ammonia per mole cyanohydrin. 5. Process according to claim 4, characterized in that it is carried out using 0.5-2 moles ammonia per mole cyanohydrin. 6. Process according to any of claims 1-5, characterized in that it is carried out at a temperature between 0 and 50or. 7. Process according to claim 6, characterized in that it is carried out at a temperature between 25 and 45nC.

Inventors: BOESTEN, WILHELMUS HUBERTUS JOSEPH, KAMPHUIS, JOHAN
Applicants: STAMICARBON B.V.
Application year: 1986
Main classification: C07C231
IPC codes: C07C235, C07C231, C07B31, C07B43, C07D521, C07C67