JPH0149694B2 - - Google Patents

Description

[Detailed description of the invention]

(Technical Field) The present invention relates to a method for producing α-oxycarboxylic acid derivatives. More specifically, it relates to a method for producing α-oxycarboxylic acid derivatives, which comprises reacting an organic halide with water, carbon monoxide, and a hydrogen donor in the presence of a basic inorganic compound and a palladium-containing catalyst. . α-oxycarboxylic acid derivatives are used in medicines such as α-amino acids and β-lactam antibiotics.
It is a group of compounds that are important as intermediates for manufacturing agricultural chemicals and various industrial products. Conventionally, compounds of this type have generally been synthesized by hydrolyzing the corresponding cyanohydrin. However, the synthesis of cyanohydrin is based on the reaction of the corresponding aldehyde with hydrocyanic acid, which requires strict care in terms of working environment and wastewater treatment, and is not an industrially preferred method. Also,
Obtaining aldehydes often requires complicated steps. (Purpose) In view of the above circumstances, the present inventors have conducted extensive research and research to develop a new method for producing α-oxycarboxylic acid derivatives using easily available raw materials.
I explored. (Structure) As a result, in the presence of a basic inorganic compound and a palladium-containing catalyst, an organic halide reacts with 2 equivalents of carbon monoxide, 1 equivalent of water, and a hydrogen donor, and in a single reaction We discovered a new and interesting reaction that yields carboxylic acid derivatives, and based on this knowledge, we completed the present invention. That is, according to the present invention, the general formula RX (R represents an organic group selected from an aryl group and a heterocyclic group, the organic group may have an inert substituent, and X represents a halogen atom) A general formula characterized by reacting an organic halide represented by ) with water, carbon monoxide, and a hydrogen donor in the presence of a basic inorganic compound and a palladium-containing catalyst
An industrially advantageous method for producing an α-oxycarboxylic acid derivative represented by RCH(OH)COOH (R is the same as above) is provided. The present invention was achieved by a novel reaction not previously described in literature, and its stoichiometry is estimated to be represented by equation (1). Base RX + 2CO + H ₂ O + 2 [H] Base ---→ RCH (OH) COOH + HX (1) The organic group R of the organic halide (general formula RX) used in the method of the present invention is an aryl group or a heterocyclic group, and this The organic radical R can be an inert substituent, for example
It may be substituted with an alkoxy group, an alkoxycarbonyl group, a hydroxyl group, an acyl group, a nitrile group, or the like. Examples of these organic groups R include phenyl group, p-tolyl group, p-methoxyphenyl group, m-phenoxyphenyl group, p-hydroxyphenyl group, p-biphenylyl group, 1-, or 2
-naphthyl group, 2- or 3-thienyl group, 2- or 3-furyl group, 2- or 5-thiazolyl group, etc. X is a halogen atom, and in view of reactivity with palladium-containing catalysts, it is preferable to use an iodine or bromine atom. The reaction of the present invention is thought to proceed according to equation (1), but it is possible to obtain a preferable rate by capturing the hydrogen halide (HX) generated during the reaction with a basic compound. Become. Any basic compound can be used as long as it has the ability to capture hydrogen halides, but hydroxides, oxides, or carbonates of alkali metals or alkaline earth metals are preferable. used. The amount of these basic inorganic compounds to be used is not limited, and even if the amount is less than the equivalent amount to the organic halide, it does not prevent the reaction from occurring.
Generally, an equivalent amount or more is used. The method of the invention is carried out in the presence of a hydrogen donor. Various so-called active hydrogen compounds can be used as the hydrogen donor, but preferably water, primary alcohol or secondary alcohol. The amount used may be less than the same mole relative to the organic halide, but usually it is used in an equal mole or more. A method in which the hydrogen donor is used in large excess to serve as a solvent is also an advantageous feature of the present invention. The method of the invention is carried out in the presence of water. The amount used is generally at least equimolar to the organic halide. However, even if the amount is less than this, it does not prevent the reaction from occurring. The reaction of the present invention proceeds at an advantageous reaction rate when carried out in the presence of a palladium-containing catalyst.
As the palladium-containing catalyst used in this case, all palladium-containing catalysts conventionally known as carbonylation decomposers can be used. Examples of these include metal palladium such as palladium black and palladium on carbon, zero-valent palladium such as tetrakis(triphenylphosphine)palladium, tetrakis(triphenylarsine)palladium, dibenzylideneacetone palladium, and carbonyltris(triphenylphosphine)palladium. Palladium complex, dichlorobis(triphenylphosphine)palladium, dichlorobis(benzonitrile)palladium, dibromobis(triphenylarsine)palladium, dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium, dichloro[1,1 ′-Bis(diphenylarsino)ferrocene]palladium, dichloro[α,ω
-bis(diphenylphosphino)alkane]palladium (alkanes are linear or branched chains with 1 to 10 carbon atoms), dichloro[α,α′-bis(diphenylphosphino)-ο-xylene]palladium , divalent palladium salts or complexes such as palladium chloride, palladium acetate, bisacetatobis(triphenylphosphine)palladium, iodophenylbis(triphenylphosphine)palladium, iodoparatolylbis(triphenylarsine)palladium, chlorobenzoylbis (triphenylphosphine)palladium, iodomethylbis(tributylphosphine)palladium, dimethyl[1,2
-Organic or hydrogenated palladium complexes such as bis(diphenylphosphino)ethane]palladium and dihydridobis(tricyclohexylphosphine)palladium can be mentioned. Any precursor that produces a chemical compound can also be used. Furthermore, a ligand such as phosphines, phosphites, phosphinites, tertiary amines, pyridine bases, bipyridyl, etc. may be added to these catalysts and used in the reaction. The amount of these catalysts to be used may be a so-called catalytic amount, and generally it is a molar ratio to the halogen compound.
Selected in the range of 0.1 to 0.00001. The present invention uses 0°C to 250°C, preferably 10°C to 200°C.
The reaction temperature is . The reaction temperature does not need to be constant and can be increased stepwise or continuously within the above range. The partial pressure of carbon monoxide is at least 0.5 atm, preferably at least 1 atm.
Carbon monoxide may contain an inert gas such as nitrogen, methane, or argon. The method of the invention can be carried out with or without a solvent. When a solvent is used, it is selected from commonly used solvents such as benzene, toluene, hexane, ether, tetrahydrofuran, hexamethylphosphorotriamide (HMPA), dibutyl ether, t-butanol, isopropanol, and the like. Separation and purification of the α-oxycarboxylic acid derivative from the reaction mixture can be easily carried out by acidifying the mixture, extracting it with an organic solvent, and then recrystallizing or distilling it. In the method of the present invention, an α-oxycarboxylic acid derivative can be easily obtained in a single reaction by carbonylating a readily available halogen compound. Therefore, from an industrial standpoint, it can be advantageously used as a new method for synthesizing α-oxycarboxylic acid derivatives. [Example] The present invention will be explained in more detail with reference to Examples below. Example 1 Iodobenzene (2 mmol), calcium hydroxide (2.5 mmol), water (0.1 ml), isopropanol (3 ml), and PdCl ₂ were placed in a 50 ml autoclave.
(PPh ₃ ) ₂ (0.02 mmol) was charged, carbon monoxide was pressurized to 150 atm at room temperature, and the mixture was reacted at 100°C for 12 hours. The mixture was acidified with hydrochloric acid, extracted with ether, and the extract was concentrated to obtain a residue containing mandelic acid. This was methylated with diazomethane and analyzed by gas chromatography, which revealed that methyl mandelate was
It was found that the product was produced at a yield of 31.3% (based on the iodobenzene used). Examples 2 to 7 In place of isopropanol and/or PdCl ₂ (PPh ₃ ) ₂ , various alcohols and/or
Table 1 shows the results of repeating the method of Example 1 using a Pd catalyst.

[Table] Example 8 Mandelic acid was obtained in a yield of 60.5% by repeating the reaction of Example 5 and recrystallizing from benzene-hexane without methylation treatment with diazomethane. Examples 9-11 Results of repeating the method of Example 1 using alkali metal hydroxide (5.0 mmol) instead of calcium hydroxide, without isopropanol, and using t-butanol (3 ml) as the solvent. are shown in Table 2. These examples show the results when water also serves as a hydrogen donor.

[Table] Example 12 The reaction of Example 5 was repeated using lithium hydroxide (5.0 mmol) in place of the calcium hydroxide in Example 5. The yield of methyl mandelate was 50.7%. Examples 13 to 15 The results of the reaction of Example 5 were repeated using various organic halides in place of iodobenzene in Example 5 and the reaction conditions listed in Table 3. Shown in the table.

[Table] Dothio
Huen
15 1〓Bro 30 140 115 47.9
monaf
Tallinn

Claims (1)

[Claims] 1 General formula RX (R represents an organic group selected from an aryl group and a heterocyclic group, the organic group may have an inert substituent, and X is a halogen atom) ) is reacted with water, carbon monoxide, and a hydrogen donor selected from water or a primary or secondary alcohol in the presence of a basic inorganic compound and a palladium-containing catalyst. The general formula RCH(OH)COOH is characterized by
A method for producing an α-oxycarboxylic acid derivative represented by (R is the same as above). 2. The method according to claim 1, wherein the halogen atom is iodine or bromine.