JPH0410460B2 - - Google Patents

Description

[Detailed Description of the Invention] The present invention relates to the general formula () (In the formula, A and B each represent a hydrogen atom, or A and B together represent a single bond.) (2R,6R)-2,6,10-trimethylundecanoic acid is useful as a synthetic intermediate for the side chain portion of optically active α-tocopherol (vitamin E),
It has been reported that it can be synthesized by a method with a large number of steps as shown below [J.Org.Chem.,
42, 3828-3832 (1977)]. The present inventors aimed to produce an optically active form of 2,6,10-trimethylundecanoic acid or 2,6,10-trimethyl-9-undecenoic acid by a simple method.
First, as a result of intensive studies on the production method of racemic forms of these compounds, we found that the general formula () which can be easily obtained from citronellol is (wherein A and B are as defined above,
X represents a halogen atom. ) by preparing a Grignard reagent from an organic halide represented by the formula and magnesium metal, and then reacting the Grignard reagent with α-methyl-β-propiolactone in the presence of a copper compound,
The present inventors have discovered that the carboxylic acid represented by the general formula () can be easily obtained in high yield, and have completed the present invention. In the method of the present invention, a Grignard reagent is prepared using an organic halide represented by the general formula () obtained from optically active citronellol as a raw material, and this is reacted with α-methyl-β-propiolactone. The resulting carboxylic acid represented by the general formula () is subjected to a hydrogenation reaction if necessary, and then optically resolved by a method known per se to obtain 2,6,10-trimethylundecanoic acid or 2,6,10- An optically active form of trimethyl-9-undecenoic acid can be easily obtained. The preparation of a Grignard reagent from the organic halide represented by the general formula () and magnesium metal can be carried out in the same manner as in the preparation of a Grignard reagent by the reaction of an ordinary organic halide and magnesium metal. For example, this is carried out by reacting an organic halide with metal magnesium in an amount of about 1 to 5 times the atomic equivalent, preferably 1 to 1.5 times the atomic equivalent, in a solvent. As the solvent, diethyl ether, diisopropyl ether, tetrahydrofuran, benzene, toluene, etc. are used, but ether solvents are preferred. The reaction temperature is approximately -10℃ + 150℃,
Preferably the temperature ranges from room temperature to about 80°C. Although there are no particular restrictions on the atmosphere of the reaction system, an atmosphere of an inert gas such as nitrogen or argon is generally preferred. Grignard reagent thus prepared and α-
A carboxylic acid represented by the general formula () can be obtained by reacting methyl-β-propiolactone in the presence of a copper compound. The amount of α-methyl-β-propiolactone used is about 0.5 to 2 times the molar amount of the organic halide represented by the general formula () used in the preparation of the Grignard reagent.
Examples of copper compounds include copper halides such as cuprous chloride, cuprous bromide, cuprous iodide, cupric chloride, cupric bromide, and their dimethylsulfides, tributylphosphine, etc. Lithium cupric chloride (Li ₂ CuCl ₄ ), copper acetate, etc. are used. The amount of copper compound used is α-methyl-β-
The amount is about 0.01 to 100 mol%, preferably 0.1 to 10 mol%, based on propiolactone. Although this reaction can be carried out in the solvent used to prepare the Grignard reagent, it is preferred to use dimethyl sulfide as a co-solvent in order to solubilize the copper compound used. After the reaction is completed, the carboxylic acid represented by the general formula () can be separated and recovered from the reaction mixture using a conventional method. For example, the reaction mixture is poured into an aqueous ammonium chloride solution, diluted hydrochloric acid is added thereto, and then extracted with hexane or the like. After washing the extract with water, a water-methanol solution of an alkali metal hydroxide such as potassium hydroxide or sodium hydroxide is added thereto, and the desired carboxylic acid is extracted into the water-methanol layer. After washing the resulting water-methanol layer with, for example, hexane, the methanol is distilled off, and the remaining aqueous layer is neutralized with dilute hydrochloric acid and extracted with ether. After drying this extract, low-boiling substances are distilled off, and the residue is distilled under reduced pressure to obtain a carboxylic acid represented by the general formula (). After subjecting the carboxylic acid represented by the general formula () obtained by the method of the present invention to a hydrogenation reaction as necessary, for example, optically active α-phenethylamine, N-benzyl-α-phenethylamine, α-
Diastereomers are generated by reacting with optically active amines such as naphthylethylamine or optically active alcohols such as l-menthol, optically active α-phenethyl alcohol, and 2-octanol, and the generated diastereomers are recrystallized. Optically active 2,6,10-trimethylundecanoic acid or optically active 2,6,10-trimethyl- 9-Undecenoic acid can be easily obtained. In addition, 2,6,10-trimethylundecanoic acid or 2,6,10-trimethyl-
2,6,10- Trimethylundecanoic acid or 2,6,10-trimethyl-
It can be an optically active form of 9-undecenoic acid. The organic halide represented by the general formula () used as a raw material is a known compound. The optically active form of the organic halide is obtained by subjecting naturally occurring optically active citronellol to a hydrogenation reaction as necessary, and then producing hydrogen halides such as hydrogen chloride and hydrogen bromide; phosphorus trichloride and tribromide. It can be easily obtained by reacting with a parogenated phosphorus compound such as phosphorus or phosphorus pentachloride; a common halogenating agent such as thionyl chloride, thionyl bromide, triphenylphosphine/carbon tetrachloride. One of the raw materials, α-methyl-β-propiolactone, is also a known compound. Methacrylic acid and hydrogen bromide are reacted to form β-bromoisobutyric acid, which is then cyclized using an aqueous sodium hydroxide solution in chloroform. It can be easily obtained by The present invention will be specifically explained below with reference to Examples. Example 1 Under a nitrogen atmosphere, 5.30 g of 1-chloro-3,7-dimethyloctane was added to a suspension of 2.4 g of magnesium metal in 3 ml of tetrahydrofuran (THF).
A solution of 24 ml of THF was added dropwise under heating under reflux for 30 minutes.
The mixture was further heated for 3 hours to prepare a Grignard reagent. The Grignard reagent obtained above was added dropwise to a solution consisting of 0.12 g of cuprous iodide, 5 ml of dimethyl sulfide, and 60 ml of THF while keeping the temperature below -5°C. Then, a solution of 2.58 g of α-methyl-β-propiolactone in 40 ml of THF was added dropwise to the reaction solution, and the mixture was stirred for 1 hour. The resulting reaction solution was poured into an aqueous ammonium chloride solution, diluted hydrochloric acid was added, and n
-Extracted with hexane. A 1N aqueous potassium hydroxide solution and a small amount of methanol were added to the hexane extract, and the resulting aqueous layer was washed three times with n-hexane.
The mixture was then acidified with dilute hydrochloric acid and extracted with diethyl ether. After drying the ether extract over sodium sulfate, the solvent was distilled off and the residue was distilled under reduced pressure to obtain 6.34 g of 2,6,10-trimethylundecanoic acid having the following physical properties (yield: 92.7).
%). NMR spectrum (90MHz) δ ^HNS _CDCl3 : 0.82 (d, J = 7Hz, 9H); 1.0-1.9 (m,
17H); 2.2-2.6 (m, 1H); 11.5 (s, 1H) Example 2 Optically active 1-chloro-3 in Example 1,
7-dimethyloctane ([α] ^23.8 _D −2.22(neat))
By carrying out the reaction and separation and recovery in the same manner as in Example 1, except for using
6.02g was obtained (yield 88%). [α] ^26.5 _D 0.13 (neat) Example 3 In Example 1, 1-chloro-3,7-dimethyloctane was replaced with 5.30 g of 1-chloro-3,7-dimethyloctane.
By performing the reaction and separation and recovery in the same manner as in Example 1 except for using 5.24 g of dimethyl-6-octene, 5.70 g of 2,6,10-trimethyl-9-undecenoic acid having the following physical properties was obtained ( Yield 84.1
%). NMR spectrum (90MHz) δ ^HNS _CDCl3 : 0.8 (d, J=6Hz, 6H); 0.9-2.1 (m,
17H); 2.17-2.55 (m, 1H) 4.9-5.16 (m, 1H); 10.95 (s, 1H) Example 4 Under nitrogen atmosphere, 0.80g of metallic magnesium
Add a small amount of iodine to 3ml of THF suspension, then add 1
-bromo-3,7-dimethyloctane 6.63g
Add a solution of 20 ml of THF dropwise under heating under reflux, and after dropping
A Grignard reagent was prepared by heating for an hour. α−
The Grignard reagent obtained above was added dropwise to a solution consisting of 2.58 g of methyl-β-propiolactone, 0.12 g of cuprous iodide, and 30 ml of THF at -20°C. After dropping, the reaction solution was heated to room temperature, poured into an aqueous ammonium chloride solution, diluted hydrochloric acid was added, and
- A 1N aqueous sodium hydroxide solution and a small amount of methanol were added to the hexane extract extracted with hexane, and the resulting aqueous layer was washed with n-hexane, acidified with dilute hydrochloric acid, and extracted with diethyl ether. After drying the ether extract over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was then distilled to obtain 5.92 g of 2,6,10-trimethylundecanoic acid.

Claims (1)

[Claims] 1. General formula (In the formula, A and B each represent a hydrogen atom or A and B taken together represent a single bond, and X represents a halogen atom.) Prepared from an organic halide represented by the following and metallic magnesium. General formula characterized by reacting a Grignard reagent and α-methyl-β-propiolactone in the presence of a copper compound (In the formula, A and B are as defined above.) A method for producing a carboxylic acid represented by the following.