JPS63258872A - Valerolactone derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (n is integer of 1-16). EXAMPLE:(2S,5R)-2-Hydroxy-5-hexyl-delta-valerolactone. USE:Various kind of chemicals or raw material for optically active compound. PREPARATION:The compound expressed by formula I is obtained by subjecting a compound expressed by formula II [* is asymmetric carbon atom) to Kolbe electrolysis with a compound expressed by formula III and then subjecting the product to cyclization. The compound expressed by formula II can be produced from a compound expressed by formula IV through a reaction process with diethyl carbonate in the presence of sodium hydride, hydrolysis process by sodium hydroxide, asymmetric reduction process of carbonyl group in the beta-position by bread yeast and reaction process with acetic anhydride in pyridine and the compound expressed by formula III is obtained by reacting S-(-)-malic acid with acetyl chloride and then reacting the product with anhydrous ethanol.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a valerolactone derivative represented by the formula (wherein n is an integer of 1 to 16, and this character represents an asymmetric carbon atom).

The compound of formula (1) is a new compound that has not been described in any literature, and the optically active form thereof is particularly useful as various reagents or raw materials for producing optically active compounds.

The compound of the formula
It can be produced by subjecting -acetoxycarboxylic acid to Kolbe electrolysis with monoethyl ester of α-acetoxy dibasic acid represented by the following formula (the ratios in the formula have the above-mentioned meanings) and cyclizing the product.

In order to produce an optically active form, the racemic form of the compound of formula I may be optically resolved, but it is preferable to use the optically active forms of the compounds of formulas (1) and (2).

The compound of formula (1) can be produced by the following method. A methyl alkyl ketone represented by the general formula (wherein n has the abovementioned meaning) is reacted with diethyl carbonate in the presence of sodium hydride, and β- Produce ketocarboxylic acid ethyl ester.

Next, β-ketocarboxylic acid ethyl ester (V) is hydrolyzed using potassium hydroxide, and when n is 4 to 16, β-ketocarboxylic acid ethyl ester (V) is converted into β - potassium ketocarboxylate, and when n is 6 or less, it is β-ketocarboxylic acid octyl ester represented by the general formula (wherein n has the above-mentioned meaning).

Next, the carbonyl group at the β-position was asymmetrically reduced using baker's yeast to obtain an optically active β-hydroxycarboxylic acid represented by the general formula (in the formula, n and * have the above-mentioned meanings), and this compound (4
) with acetic anhydride in pyridine, an optically active β-acetoxycarboxylic acid of formula (1) is obtained.

It can also be produced by alcoholysis of an optically active β-hydroxycarboxylic acid in which n is 1 or an optically active poly-β-hydroxybutyrate.

Monoethyl ester of optically active α-acetoxy dibasic acid (Ill) can be produced by reacting S-(@-maricic acid) with acetyl chloride and reacting the product with absolute ethanol (tetrahedron 41, A13
．． 2751-2758.1985). The formula for this reaction is as follows.

When producing the optically active substance of formula I, first, the compound of formula (1) is reacted with the compound of formula (2) using an electrode by Kolbe electrolysis method to form a compound represented by the general formula (n and * in the formula have the above meanings). Manufacture a compound.

It is advantageous to use an optically active compound as at least one of the compounds of formula (1) and (2). Kolbe electrolysis is preferably carried out in methanol in the presence of sodium.

The compound of formula X is then cyclized to give the optically active form of formula I. Preferably, the compound of formula X is cyclized in the presence of p-toluenesulfonic acid.

The optically active substance of formula (2) thus obtained can be isolated and purified by column chromatography, recrystallization, etc.

Reference Example 1 Synthesis of β-acetoxynonanoic acid Diethyl carbonate 210ml. 12°8 g of sodium hydride at a concentration of 60% by weight dispersed in oil and 7100 m of dioxa
A solution of 20.0 g% of methylhexyl ketone (°C) dissolved in 100 mJ of dioxane was added dropwise to the solution consisting of 1 under an argon atmosphere, and after refluxing overnight, the solvent was removed.
Distilling the residue under reduced pressure yields 20 ethyl hexylketoacetate,
Og was obtained. 0.65 Hg, 86°C1 Yield 62
．． 5%.

15 J of ethyl hexylketoacetate was added to 75 ml of ethanol.
After dissolving in a solution consisting of 75 ml of distilled water and 5.02 g of potassium hydroxide and stirring at room temperature for 15 hours, 31.0 ml of distilled water was added to this solution. ffi sugar 660g and dry yeast 168. ．． 9 was added, and the mixture was shaken at 60°C for 16 hours, and then filtered through Celite. The precipitate was air-dried, extracted with ethyl acetate, and the extract was concentrated. Also, add hydrochloric acid to the filtrate and p
H1, added common salt to make a saturated solution, extracted with chloroform, concentrated the extract, dissolved in diethyl ether together with the above concentrated solution, extracted twice with 1N sodium hydroxide solution, and then extracted with hydrochloric acid again. and salt to make a saturated brine solution with pH 1, extracted five times with ether, washed the ether layer with saturated brine, dried over magnesium sulfate, evaporated the ether, and recrystallized from n-hexane. β-hydroxynonanoic acid 7, 81,! i+ was obtained. Melting point 496-50.0° C1[α]24°de+20.1° (c=1.1, CHCl3).

To 5.0 g of this β-hydroxynonanoic acid, 2
0 ml and 3.2 ml of acetic anhydride were mixed under water cooling, stirred overnight at room temperature, cooled on ice, added 5 ml of distilled water, then dissolved in 1N hydrochloric acid, extracted with ether, and the ether layer was saturated. Washed with brine and dried over magnesium sulfate. The ether is then evaporated and concentrated to give β-
5.4 g of acetoxynonanoic acid was obtained.

Reference Example 2 Synthesis of β-acetoxybutanoic acid 5 g of optically active poly-β-hydroxybutyrate was mixed with 36 g of absolute ethanol.
ml and 56 ml of anhydrous 1,2-dichloroethane, 1.1 ml of concentrated sulfuric acid was added, and the mixture was heated under reflux for 57 hours. After cooling, 15 ml of saturated brine was added, Celite was suspended, and the mixture was filtered. Solution F was diluted once with 7Qml of ether and 2Q
Extracted 3 times with 1ml of ether, leaving 1ooml of residue! The extract was combined with the extract, washed with saturated sodium bicarbonate solution and saturated brine, and dried over magnesium sulfate. After removing the ether, distillation under reduced pressure yields (R)-β-hydroxybutanoic acid ethyl ester 4.
．． 08 was obtained.

[α]21°’=+43.9°.

(R)-β-hydroxybutanoic acid ethyl ester4. Low water 15m/,! It was dissolved in a mixed solution consisting of 15 ml of Tanoh YV and sodium hydroxide, heated under reflux for 6 hours, cooled, and mixed with ion exchange resin (・7 Amberly) I.
R-120B), the solvent was removed under reduced pressure. 1Q ml of anhydrous pyridine and 3 ml of acetic anhydride were added to the residue, and the mixture was left at room temperature overnight. Add dilute hydrochloric acid to the reaction solution to adjust the pH.
1, saturated with common salt, extracted with chloroform,
The extract was washed with saturated brine and then dehydrated over magnesium sulfate. Then, chloroform was removed under reduced pressure to obtain the desired product 3.6I. [α]o=-5,7° Reference Example 6 160 ml of acetyl chloride was added to 50 g of (S)-(-)-maricic acid, and after stirring and refluxing at 55°C for 4 hours, the solution was concentrated under vacuum. Add 100 ml of benzene to the residue, remove benzene and acetic acid under vacuum, concentrate, cool to room temperature, and add 100 ml of absolute ethanol to the residue.
1, stirred vigorously while cooling occasionally, and then
Heated at ~75°C for 10 minutes and 50-55°C for 10 hours. Next, the solvent was removed under reduced pressure, and the remaining residue was separated and purified using a silica gel column using methylene chloride-methanol (50:1) as a developing solvent. Obtained. Melting point 50-51°C, [α] = -61.6° (c = 1
．． 42, ethane).

Example 1 (R)-β-acetoxynonanoic acid synthesized in Reference Example 1 and Reference Example 3: 1.89,! 7 and s-(2)-acetoxybutane deoic acid 1-ethyl ester 7, 14
Dissolve g in methanol and add 26.2 rng of sodium.
In addition, using Yanaco constant potential electrolyzer VE-8,
Kolbe electrolysis was performed for 7 hours under the conditions of 20 to 60°C, 30V, and 1.5A. After the electrolysis, 40 ml of 6N sodium hydroxide solution was added, stirred overnight, methanol was removed, and extracted with ether. Hydrochloric acid was added to the separated aqueous alkali layer to bring the pH to 1, and then common salt was added to saturate. The crude 6,6
1.51 of -cyhydroxyandecylcarboxylic acid were obtained. This product was dissolved in benzene iQml, added with a catalytic amount of p-toluenesulfonic acid, stirred at room temperature for 2 hours, then dissolved in ether and diluted with saturated aqueous sodium bicarbonate solution for 3 hours.
After washing twice and then once with saturated saline, it was dried over magnesium sulfate, the ether was evaporated, and the concentrated product was separated and purified using a silica gel column using a mixture of hexane and ethyl acetate as a developing solvent. - When recrystallized from a mixed solvent of hexane and ethyl acetate, (2S, 5R
) -2-Hydroxy-5-hexyl-δ-valerolactone 245.11n9 was obtained. The infrared absorption spectrum of this compound is shown in FIG.

Melting point near 5.5-77.0'C Elemental analysis value: CHN Experimental value 65.84 10.29 0.06 Theoretical value 6
5.47 10.07 0 Specific optical rotation: [α]” = + 76.8° (in chloroform, c = 1.1) “H-NMR: δppm 446 (2H), 3.21 (IH), 1 .31 (14H
), 0.89 (3H) Example 2 2.92 g of (R)-β-acetoxybutanoic acid synthesized in Reference Example 2 and Reference Example 6 and S-(2)-acetoxybutane deoituccinic acid 1-ethyl ester 16 Dissolve .5g in 40rnl of methanol, 59.8mg of sodium
was added, and Kolbe electrolysis was performed at 60°C for 5.5 hours. After removing methanol under reduced pressure, 3 Q ml of anhydrous pyridine and 10 ml of acetic anhydride were added, and the mixture was allowed to stand at room temperature overnight, diluted with diluted hydrochloric acid until the pH reached 1, salt was added to make a saturated solution, and the mixture was extracted with chloroform. After washing the extract with saturated saline and dehydrating over magnesium sulfate, chloroform was removed under reduced pressure, and the residue was purified using a silica gel column.
When developed with a mixed solvent consisting of hexane and ethyl acetate, 850 ml of (2R)-(SR)-diacetoxyhexanoic acid ethyl ester was obtained. This ester was dissolved in 2Q ml of methanol, 12 ml of 1N sodium hydroxide solution was added, and the mixture was left at room temperature overnight, passed through an ion exchange resin (Amberlite IR-120B), and the solvent was removed. 4 so mg of (2S)-(SR)-dihydroxyhexanoic acid was obtained. This hydroxy acid was dissolved in 10#Il of 1N hydrochloric acid, stirred at room temperature for 2 hours, saturated with common salt, extracted with chloroform, and the extract was washed with saturated brine and dehydrated over magnesium sulfate. After removing chloroform under reduced pressure,
The residue was developed using a silica gel column with a mixed solvent of chloroform and methanol to isolate the desired product, and then recrystallized from diethyl ether to obtain (28,5R)-2
-Hydroxy-5-methyl-δ-valerolactone56.
4 m9 was obtained.

The infrared absorption spectrum of this compound is shown in Figure 2.0 Melting point: 37.4-39.0°C Elemental analysis value: HN Experimental value 55.75 7.01 0.10 Theoretical value 55
．． 80 7.060 Specific rotation: [α:) = +87.5°'H-NMR: δppm 1.64.1.41 (d, 3H), 1.50-2.50
(m, 4H), 3.60 (s, IH), 4.20~4
．． 70 (m12H)

[Brief explanation of drawings]

FIG. 1 is a graph showing the infrared absorption spectrum of the compound obtained in Example 1, and FIG. 2 is a graph showing the infrared absorption spectrum of the compound obtained in Example 2.

Claims (1)

[Claims] 1. A valerolactone derivative represented by the general formula (numerical formula, chemical formula, table, etc.) (I) (in the formula, n represents an integer from 1 to 16). 2. The compound according to claim 1, wherein n is 6. 3. The compound according to claim 1, wherein n is 2.