JPS5917095B2 - Method for producing optically active α-substituted carboxylic acid - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing optically active α-monosubstituted carboxylic acids.

Organic compounds having asymmetric carbon atoms have a pair of optical antipodes, but it is known that most organic compounds obtained from nature have only one optical antipode.

In recent years, it has been revealed that a pair of optical antipodes have different physiological activities [for example, Toshio Yoshida et al.
Kagaku Review, Vol. 14, p. 169 (1976)]. Therefore, in industrial fields such as perfumes, medicines, and agricultural chemicals, the importance of optically active substances containing a large amount of one optical i0 enantiomer has been recognized. The optically active d-monosubstituted carboxylic acid represented by the general formula of the present invention is considered to be a very effective substance as an intermediate for the synthesis of such optically active substances [for example, in "Atlas J5 Offset" by Kline (W.・Stereochemistry
emistry), pp. 5 and 45, Chapman and Hall (previously,
As a method for producing optically active d-monosubstituted carboxylic acids represented by the general formula, optical resolution methods [for example, Pettersson (
K. Petterss On) et al., ArkivfOrKemi, Vol. 9, p. 333 (
1956) and C. AarOn et al., Journal of Organic Chemistry 1 (Jou
rnalOfOrganicChemistry) 3rd
2, p. 2797 (1967)], methods by derivation from other types of optically active compounds [for example, Brewster (P
．． Brewster etc., Nature
166, p. 178 (1950)], or asymmetric synthesis methods [for example, A.I.
), etc., Journal of the American Chemical
Society (JournalOftheAnleri)
canChemicalSOciety) Volume 98, 5
67 (1976) and Myers (A.I.Me
37ers), etc., Tetrahedron. Letters (Tetr)
ahedrOnLetters) 3495 pages (1974
year)] is known.

However, the optical resolution method has the disadvantage that recrystallization must be repeated many times, requiring a great deal of effort and time. In addition, when deriving from other types of optically active compounds, it is limited to cases where a suitable optically active compound is easily available as a synthetic raw material, so it is not only not general, but also expensive as a raw material, making it economically uneconomical. It is disadvantageous. In addition, methods using asymmetric synthesis have the disadvantage that the optical yield is extremely low or that it is difficult to hydrolyze the synthetic intermediate, and the reaction yield is low. The object of the present invention is to overcome the drawbacks of the above-mentioned conventional methods and to provide a method for efficiently producing an optically active α-monosubstituted carboxylic acid represented by the general formula.

That is, the present invention is based on the general formula [1] (wherein R is a phenyl group or a chlorine atom, and R' is C1-
Indicates the alkyl group of ClO.

) is reacted with lower alkyl lithium, protons are added to the reaction product, and then hydrolyzed to form the general formula (R
represents a phenyl group or a chlorine atom, and k represents an alkyl group of C1 to ClO. ) to produce an optically active α-monosubstituted carboxylic acid. Next, the present invention will be explained in detail.

First, the oxazoline derivative represented by the general formula [1] is (S)-phenylalaninol [e.g.
Chemical and Pharmaceutical Bulletin (Ki) etc.
icalBulletin) et al. 13 volumes, 995 pages (19
1965)] as a raw material [for example, A.I. Meyers et al., Journal of the
American Chemical Society (JOumalO)
ftheAnlericanChemicalSOci
ety) Vol. 98, p. 67 (1976)].

After dissolving this oxazoline derivative [D] in a pre-dried organic solvent such as tetrahydrofuran, ether, dioxane, etc.,
Cool to ℃ using dry ice. Lower alkyl lithium, such as n-butyl lithium, Sec-butyl lithium, tert-butyl lithium, phenyl lithium, etc., is added dropwise to the cooled solution under an inert gas flow of nitrogen, argon, or the like. Among these lower alkyllithiums, n-butyllithium is the most preferred from operational and economical standpoints. Lower alkyl lithiums are usually used as hexane, cyclohexane, pentane, or benzene-ether solutions. The molar ratio of the lower alkyl lithium to the oxazoline derivative used is substantially equimolar, preferably 1 to 1.
It is 1.2 mol. This mixture is heated for at least 5 minutes, preferably 1
Stir and react under the same inert gas flow as above for 0 to 60 minutes. The reaction temperature is preferably 20°C or lower, and protons are preferably added to the reaction product to asymmetrically change the oxazoline derivative [
For example, E. L. Ellel, "Stereochemistry of Carbon Compounds", p. 48, Tokyo Kagaku Dojin (1977).
] This protonation is performed when the reaction mixture contains a large excess of water, alcohols such as methanol, ethanol, propanol, etc.
This can be easily achieved by adding organic acids such as acetic acid, propionic acid, butyric acid, but water is most preferred for operational reasons.
The asymmetrically modified oxazoline derivative is extracted from the reaction mixture after the proton addition using an organic solvent such as ether, ethyl acetate, or benzene. Dissolve this oxazoline derivative in 0.5-6N mineral acid such as hydrochloric acid or sulfuric acid and
Hydrolyze by heating to 70°C to 110°C for ~5 hours. Next, this hydrolysis reaction solution is extracted with an organic solvent such as ether, ethyl acetate, or benzene, and an optically active α-monosubstituted carboxylic acid represented by the general formula can be obtained from this organic solvent layer. Further, if necessary, it can be purified by the method described below. That is, the target carboxylic acid extracted with an organic solvent after the hydrolysis reaction is further extracted from the organic solvent layer with an aqueous alkaline solution such as sodium hydrogen carbonate or potassium carbonate, and then this alkaline layer is made acidic (PHl) with hydrochloric acid, and then the organic solvent is extracted again with hydrochloric acid. Extract with solvent. The organic solvent layer is dried over sodium sulfate, concentrated, and the residue is distilled to obtain a highly pure α-monosubstituted carboxylic acid. According to the method of the present invention, an optically active d-substituted carboxylic acid represented by the general formula can be easily obtained with an optical yield of 30% or more.

This method can be carried out without complicated operations as in the optical resolution method, and there is no decrease in yield during the hydrolysis process as in the method of asymmetric synthesis, and there is no extreme decrease in optical yield. This is a clear advantage compared to known methods.
Example 1 (4S)-2-(1-phenylpropyl)-4-benzyl-2-oxazoline (RC6H5 in formula 1, R'=C2
H5 compound) 22.3t was dissolved in 80ml of dry tetrahydrofuran and mixed with -78g in a dry ice-acetone bath.
Cooled to ℃.

68.6 ml of a 1.4M n-butyllithium hexane solution was added dropwise to this solution over 10 minutes under an argon stream, and the mixture was stirred at -78°C for 45 minutes. While stirring, 40 ml of water was added to the reaction mixture containing a yellow precipitate produced by the reaction to add protons and asymmetrically change the oxazoline derivative. The reaction mixture was poured into 0.81 g of water and extracted with ether (300 m2 x 4 times). After washing the ether layer with saturated brine, the ether was distilled off and the residue was dissolved in 6N sulfuric acid.
．． 81 and heated under reflux for 4.5 hours. The reaction solution was cooled to room temperature and extracted with ether (300ml x 5 times).
The ether layer was further extracted with a 5% aqueous sodium hydrogen carbonate solution (300ml x 4 times). This alkaline aqueous solution was made acidic (PHI) with 6N hydrochloric acid, and then extracted with ether (300ml x 4 times) again. This ether layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was distilled to obtain 2-phenylbutyric acid of 9.87% (reaction yield: 74%). The spectral data were completely consistent with the 2-phenylbutyric acid standard. The optical rotation of the obtained acid is (4)
5+39.22.6, benzene) and the optical yield is 40%
, the absolute configuration was (S). Example 2 (4S)-2-(1-phenylhexyl)-4-benzyl-2-oxazoline (formula α) with R-C6H5, R'-
35.3 t of C5Hll compound) was dissolved in 110 ml of dry tetrahydrofuran and cooled to -78°C in a dry ice-acetone bath.

94.3 ml of a 1.4 Mf) n-butyllithium hexane solution was added dropwise to this solution over 10 minutes under an argon stream, and the mixture was stirred at -78°C for 45 minutes. 55 ml of water was added to this reaction mixture to add protons and cause an asymmetric change in the oxazoline derivative. This reaction mixture was poured into 1.11 ml of water and extracted with ether (400 ml x 4 times). After washing the ether layer with saturated brine, the ether was distilled off, and the residue was dissolved in 1.11 parts of 6N sulfuric acid and heated under reflux for 4.5 hours. This reaction solution was cooled to room temperature and then extracted with ether (40%
The ether layer was extracted with a 5% aqueous potassium carbonate solution (400 ml x 4 times). This alkaline aqueous solution was made acidic (PHI) with 12N hydrochloric acid, and then extracted with ether (400ml x 4 times) again. This ether layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was distilled to give 18.8y (reaction yield 8
3%) of 2-phenylheptanoic acid was obtained. The spectral data were completely consistent with the 2-phenylheptanoic acid standard.
The optical rotation of the obtained acid is (b) sweet + 37.7 points (CO.8
8, benzene), the optical yield was 53%, and the absolute configuration was S. Example 3 119t of (4S)-2-(1-chloroethyl)-4-benzyl-2-oxazoline (a compound of R=Cl.R'=CH3 in formula 1) was dissolved in 80d of dry tetrahydrofuran and mixed with dry ice-acetone. Cooled to -78°C in a bath.

62.9 ml of a 1.4Mf) n-butyllithium hexane solution was added dropwise to this solution over 10 minutes under an argon stream, and the mixture was stirred at -78°C for 25 minutes. 16 d of water was added to this reaction mixture to add protons and cause an asymmetric change in the oxazoline derivative. The reaction mixture was poured into 0.81 g of water and extracted with ether (250 ml x 4 times).
After washing the ether layer with saturated brine, the ether was distilled off, and the residue was dissolved in 530 ml of 1N hydrochloric acid and stirred for 1.5 hours at 80 mL.
heated to ℃. After cooling the reaction solution to room temperature, it was extracted with ether (400ml x 5 times), and this ether layer was extracted with a 5% aqueous sodium bicarbonate solution (400ml x 4 times).
This alkaline aqueous solution was made acidic (PHI) with 6N hydrochloric acid, and then extracted with ether (400a x 5 times) again. This ether layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was distilled to obtain 6.8 t (reaction yield: 78%) of 2-chloropropionic acid. The spectral data were completely consistent with the 2-chloropropionic acid standard. The optical rotation of the obtained acid is (4) +7.00 (C5
．． 44, methanol), the optical yield was 50%, and the absolute configuration was (YQ. Example 4 (4S)-2-(1-chloropentyl)-4-benzyl-2-oxazoline (formula [
1], the compound 26.67 with R=Cllbi=C4H was dissolved in 100 ml of dry ether and cooled to 40 DEG C. in a dry ice-acetone bath.

64.7 ml of a 1.7Mf) tert-butyllithium benzane solution was added dropwise to this solution over 15 minutes under a nitrogen stream, and the mixture was stirred at -40°C for 15 minutes.

30 ml of methanol was added to this reaction mixture to add protons and cause an asymmetric change in the oxazoline derivative. After pouring this reaction mixture into 11 water, benzene extraction (
300m 1 x 4 times). After washing the benzene layer with saturated saline, the benzene was distilled off, and the residue was soaked in 400 ml of 1N hydrochloric acid!
It was dissolved in Ll and heated to 80°C for 1.5 hours. After cooling the reaction solution to room temperature, it was extracted with benzene (150 ml x 5 times), and this benzene layer was extracted with a 5% aqueous sodium bicarbonate solution (150 ml x 4 times). This alkaline aqueous solution was made acidic (PHI) with 6N hydrochloric acid, and then extracted with benzene (150ml x 5 times) again. This benzene layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was distilled to obtain 9.87 (reaction yield: 65%) of 2-chlorohexanoic acid. The spectral data were completely consistent with the 2-chlorohexanoic acid standard. The optical rotation of the obtained acid was Cct)27+5.3 (C4.2, methanol), the optical yield was 45%, and the absolute configuration was (8).

Claims (1)

[Claims] 1 General formula [I] ▲ Numerical formulas, chemical formulas, tables, etc.▼ (In the formula, R is a phenyl group or a chlorine atom, R' is C_1
~C_1_0 represents an alkyl group. ) is reacted with a lower alkyl lithium, a proton is added to the reaction product, and then hydrolyzed.
I]▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R is a phenyl group or a chlorine atom, R' is C_1
~C_1_0 represents an alkyl group, and the carbon to which the benzyl group of the oxazoline ring is bonded has either (S) or (R) configuration. ) A method for producing an optically active α-substituted carboxylic acid.