JPS6233136A - Optically active gamma-alkyl-alpha-acyloxycarboxylic ester and production thereof - Google Patents

Abstract

NEW MATERIAL:An optically active gamma-alkyl-alpha-acyloxycarboxylic ester shown by the formula I(R<1>, R<2> and R<3> are the same or different lower alkyl each; C* is asymmetric carbon atom). EXAMPLE:An (R)-(+)-acyloxycarboxylic ester. USE:Useful as a precursor for an optically active beta-alkyl-gamma-butyrolactone suitable as a raw material for synthesizing optically active vitamin E, vitamin K, terpene compound such as dolichol, etc., and its analogs. The compound shown by the formula I is hydrolyzed and optionally treated with an acid to give the butyrolactone. PREPARATION:A beta-alkyl-delta-ketocarboxylic acid ester shown by the formula II is reacted with trifluoroperacetic acid in a halogenated hydrocarbon solvent such as methylene chloride, etc., preferably at 0 deg.C - room temperature, to give a compound shown by the formula I.

Description

[Detailed description of the invention] Industrial applications The present invention is based on the general formula %formula% (In the formula, R1, R2 and R3 are the same or different.

Each represents a lower alkyl group, and *C represents an asymmetric carbon atom. ) The present invention relates to an optically active β-alkyl-γ-acyloxycarboxylic acid ester (hereinafter referred to as acyloxycarboxylic acid ester (1')) represented by the following formula and a method for producing the same.

The novel acyloxycarboxylic acid ester (1) provided by the present invention is an optically active vitamin E1.
The optically active β compound represented by the general formula is useful as a raw material for the synthesis of terpene compounds such as dolichol and their analogs.
It is useful as a precursor of -alkyl-γ-butyrolactone (hereinafter referred to as butyrolactone/(U)).

BACKGROUND OF THE INVENTION Although acyloxycarboxylic acid ester (1) is a new compound that has not been described in any literature, several methods for synthesizing butyrolactone (II) derived from this compound are known.

For example, C. B. Chapleo et al., J. Che.
rn, Sac,.

Perkin I, 1977, 1211-121
On page 8, starting from methyl hydrogen (t)-3-methylglutarate, iodide (1odo-es
(S) -(
-)-3-methyl-4-butanolide was obtained.

In addition, the following method using (E)-(2R,3S)-6-ethylidene-3,4-dimethyl-2-phenylperhydro-1,4-oxazepine-5,7-dio/ as a starting material was also reported by Mende et al. A method is disclosed. In addition, in the following, ph%Ac and Me represent a phenyl group, an acetyl group, and a methyl group, respectively, DMF means dimethylformamide, and THF means tetrahydrofuran.

(Chemistry Letters, 1979, pp. 1207-121o) (Chemistry Letters, 1979, pp. 1207-121o)
In addition to these synthetic methods, ethyl trans-4,4-dimethoxy-3-methyl-crotonate was synthesized from beer yeast (Sa.
ccharomyces cerevisiae) and microbiologically (S)-(-)-3-methyl-4
- Conversion to butanolide by the method of Richard Berner et al. [JP-A-52-136102; He1v,
Chim.

kct&, 62,455 (1979)), isobutyric acid microorganism (Candida rugosa IFO075)
0) Kyoru oxide was converted to methyl ester (R)
Mori's method using -(-)-3-hydroxy-2-methylglopionate as a raw material: (In the above formula, THP represents a tetrahydropyranyl group, and Ts represents a p-toluenesulfonyl group.) (Tetrahedron Lett,, 39.31
07 (1983)] are known.

Problems to be Solved by the Invention The method of Chapleo et al. can only be used for the synthesis of (S)-(-')-type compounds from the viewpoint of starting materials; ) (There are problems such as the need to use 5.3 k7 of iodine and 4.2 kg of silver acetate to synthesize 1 kg of 3-3-methyl-4-butanolide, and as an industrial production process. In addition, in the method of Mende et al., it is extremely difficult to mass synthesize the starting material crab, which has an extremely complex chemical structure. Furthermore, in addition to the expensive raw materials used in the method of Lich/Ruth Berner et al., the conversion rate to the target compound can only reach around 50% even over a long period of time. Furthermore, due to the specificity of the fermentation reaction, Mori's method has problems such as being effective only for producing (S')-type compounds. Since it is used as an (S')-type compound, it can only be used for producing (S')-type compounds, and the raw materials and reaction reagents are expensive.

Therefore, one object of the present invention is to provide (S) integral or (
The object of the present invention is to provide an optically active β-alkyl-γ-acyloxycarboxylic acid ester that can be derived into R) monolithic petirolac), /(It) in a good yield. Another object or target of the present invention is that the optically active β-alkyl-
It is an object of the present invention to provide a method for easily producing γ-acyloxycarboxylic acid ester with good yield.

According to the present invention, the above object is achieved by providing an acyloxycarboxylic acid ester (1) as described above and having the general formula %, where R1, R2, R3 and C are as defined above. An acyloxycarboxylic acid characterized by treating an optically active β-alkyl-δ-ketocarboxylic acid ester (hereinafter referred to as δ-ketocarboxylic acid ester (III)) shown in (1) with trifluoroperacetic acid. ester (1)
This is achieved by providing a manufacturing method.

The lower alkyl groups represented by R1, R2 and R3 in each of the above general formulas include methyl group, ethyl group,
Examples include propyl group, isopropyl group, and butyl group.

δ-Ketocarboxylic acid ester (In
) is preferably treated with trifluoroperacetic acid to synthesize acyloxycarboxylic acid ester (1), reaction 1d, is carried out in a halogenated hydrocarbon solvent such as methylene chloride or chloroform. The amount of solvent used is not critical, but
δ-ketocarboxylic acid ester (approximately 1 to Ill'l)
100 times the weight, preferably about 5 to 20 times the weight. The reaction temperature ranges from about -30°C to the boiling point of the solvent used, preferably from 0°C to room temperature (about 20°C). The reaction time depends on the reaction temperature used, but is usually about 10 to 30 minutes.
It takes about an hour. The trifluoroperacetic acid used in this reaction can be easily obtained by reacting about 30 to 90% hydrogen peroxide and trifluoroacetic anhydride in methylene chloride at a temperature of about 10°C to room temperature. . The amount of trifluoroperacetic acid used is δ-ketocarboxylic acid ester (I
1 molar equivalent or more, preferably 1.5 to 2 molar equivalents to II)
．． 0 molar equivalent.

After completion of the reaction, isolation and purification of the product from the reaction mixture can be carried out by methods commonly used for isolation and purification of organic compounds. For example, after adding saturated sodium bicarbonate solution to the reaction mixture and stirring thoroughly, the organic layer is separated, and the aqueous layer is thoroughly extracted with a solvent. Combine the organic layers and add 5% thiosulfate) IJ
The crude product of diacyloxycarboxylic acid ester (1) is obtained by sequentially washing with aqueous sodium chloride solution and saturated brine, drying over anhydrous magnesium sulfate, and distilling off the solvent under reduced pressure. This crude product is purified as it is or by operations such as chromatography and distillation, and then subjected to a hydrolysis reaction as described below, and then treated with an acid as necessary to produce the above-mentioned butyrolactone (It'). can lead.

The δ-ketocarboxylic acid ester (In) used as a raw material in the method of the present invention is, for example, 1-amino-2-methoxymethylpyrrolidine (S) or (R) reported by Enders et al. (hereinafter referred to as SAMP). It is easily synthesized using dialkyl methyl ketone as a raw material (Te
trahedron Lett,, 24.4967
(1983)]. A method using RAMP is shown below.

(In the above formula, LDA means lithium diisopropylamide, and R1 and R2 are as defined above.) After hydrolyzing the acyloxycarboxylic acid ester (1) provided by the present invention, Butyrolact/(■) by treating the product with acid if necessary
O-acyloxycarboxylic acid ester (1) derived from
The hydrolysis reaction is carried out in alcoholic solvents such as methanol and ethanol, in the presence of basic compounds such as alkali metal carbonates such as potassium carbonate and sodium carbonate, and alkali metal hydroxides such as potassium hydroxide and sodium hydroxide. It is preferable to do so. As the basic compound, it is particularly preferable to use an alkali metal carbonate. The amount of the solvent used is not critical, but it is about 1 to 100 times the weight, preferably about 5 to 20 times the weight of the acyloxycarboxylic acid ester (per 1'l). Approximately 0.01 to 1 for (1)
molar equivalent, preferably 0.1 to 0.5 molar equivalent.

The reaction temperature is preferably in the range from room temperature to around the boiling point of the solvent, and the reaction time depends on the reaction temperature, but is usually 3 to 24 hours.
It takes about an hour. It is suitable for determining the reaction time to follow the progress of the reaction by thin layer chromatography (TLC) and confirm the disappearance of the raw materials. After the reaction is completed, the solvent is distilled off from the reaction mixture under reduced pressure, and the resulting residue is examined by TLC. If a spot of γ-hydroxycarboxylic acid, which is a hydrolysis product, is observed, the next treatment with acid is performed. provide This acid treatment is preferably carried out in a solvent. As the solvent, it is preferable to use 710 genated hydrocarbon solvents such as chloroform and methylene chloride, aromatic hydrocarbon solvents such as benzene and toluene, and ether solvents such as tetrahydrofuran and 1,2-dimethoxyethane. be. The amount of solvent to be used is not critical, but it is about 5 to 100 times the weight, preferably about 1 to 100 times the weight of the acyl 7-carboxylic acid ester. Examples of acids include para-toluenesulfonic acid, benzenesulfonic acid, etc. Acids soluble in organic solvents, strongly acidic ion exchange resins, etc. can be used.The amount of acid used is in excess of the amount of basic compound used in the hydrolysis reaction, preferably from about 1.2 to 1.8 times the molar equivalent.The reaction temperature is preferably in the range from room temperature to around the boiling point of the solvent, and the reaction time depends on the reaction temperature, but is usually about 3 to 24 hours.After the reaction is completed, the reaction mixture After cooling and separating the generated insoluble materials, the F solution is concentrated under reduced pressure to obtain a crude product of buty-alpha-lactone (I[).This crude product can be subjected to operations such as chromatography and distillation. It can be purified.

Example Hereinafter, the present invention will be explained in detail using examples.

Among instrumental analyses, 'H-NMR uses CDα3 as a solvent;
Measurements were made using tetramethylsilane as an internal standard, and IR was measured using a liquid film.

Example 1 35% hydrogen peroxide solution 1.6 ILl! methylene chloride 6
In addition to yxl, 18.79 g of trifluoroacetic anhydride was added dropwise to the resulting mixture under water-cooling and stirring.
．． A methylene chloride solution of trifluoroperacetic acid was prepared by stirring for 5 hours, and R1 in the general formula (lI[) was added to this solution.
, R2 and R3 are each a methyl group, and Ca
)20+ 3.3 s (neat) (S)-(+)-δ-ketocarboxylic acid ester 1.
A methylene chloride solution (10 m/m) of 715' was added dropwise to the mixture under water cooling, and the mixture was stirred at room temperature for 20 hours. Saturated sodium bicarbonate solution 20
After adding 0d and stirring well, the organic layer was separated.

The aqueous layer was extracted three times with 100 g of methylene chloride. The organic layers were combined, washed successively with 150 d of 5% sodium thiosulfate aqueous solution and 100 d of saturated brine, and then dried over anhydrous magnesium sulfate. By distilling off the solvent under reduced pressure, 1.80 f of a yellow liquid was obtained. This liquid was subjected to silica gel column chromatography [hexane/ethyl acetate = 10/1
(volume ratio) was used as a developing solution] to obtain 1.532 (81% yield) of a colorless liquid. According to the analysis results below, this product has general formula (1) in which R1, 12 and R3 are each methyl groups (R) -(+)-
It was confirmed that it was an acyloxycarboxylic acid ester.

'H-NMR: δp-1,00 (3H, d, J=7H
z, CH3).

2.06(3H,s, 0(3CH3), 2.0~2
．． 6 (3H, m, CH2°CH), 3.69 (3H,
s, 0CHs), 3.87 (IH, dd, J=11Hz
, J=6.4Hz, 0CH2), 4.05(IH
,dd, J=11Hz, J==5.6Hz, 0C
R2) IR: 1735crIL-1 MS: 175 (M+1) [α几' -1-3,4° (C=3.0.C Showa 3) Reference Example, 1 (R) -( obtained in Example 1) +)-Acyloxycarboxylic acid ester 1. Soy was dissolved in 15x methanol, 240 ml of anhydrous potassium carbonate was added to this solution, and the mixture was heated under reflux for 20 hours. After distilling off the solvent under reduced pressure, chloroform 50ml and para-toluenesulfone @0 were added to the residue.
．． 5f was added and heated under reflux for 10 hours. After cooling, the insoluble matter was separated and the P solution was concentrated under reduced pressure to obtain 1.02 f of a yellow liquid.

This liquid was purified by silica gel column chromatography [hexane/ethyl acetate = 20/1 (volume ratio) was used as the developing solution], and then purified using a Kugelrohr distillation device (external temperature: 18
A colorless liquid of 680 ml (yield: 79 ml) was obtained by distillation using 5° C. and 158 mA (R9). The following analysis results confirmed that this product was (R)-(+)-butyrolactone in which R2 was a methyl group in general formula (II).

LH-NMR: appnll, 16 (3H, d, J=
6.4Hz, CHa).

1.8-2.9 (3) 1. m, C1(2,CH),
3.88 (114, dd, J=8.8H7゜J=6
．． 4Hz, 0CH2), 4.42(IH, dd,
J=8.8Hz, J=7.2Hz.

0C)i2) IR:1765α-1 MS:1100('') CαID0+ 25.0'' (C=4.0, CH
The literature value for the optical rotation of (S)-(-) with optical purity of 97% is [α-24,70 (C=4.sOH)].
0. C'HsOH) (Helv, Chim, A
cta4.62.455 (1979) ) or (α)
:1-24.960 (C=1.771.CHsOH)
(Tetrahedron Lett, 39,310?
(1983)).

Example 2 In the general formula (III) used in Example 1, R
1, R2 and R3 are each a methyl group [α]2
(S)- with an optical rotation of 0+3.35° (neat)
Cab: o-a, s 5° (n
eat) cD optical rotation f&wosuru (R)-<-)-δ-ketocarboxylic acid ester 1.71f was used.
'%). This item is IRlN except for the optical rotation shown below.
Since the analysis results of MR and MS agreed well with the analysis results of the acyloxycarboxylic acid ester obtained in Example 1, R1, R2$, and R3 in general formula (1) are each a methyl group (S) It was confirmed that -(-)-acyloxycarboxylic acid ester.

[α) 23-3.4° (C=a, o, CHα3)
Reference Example 2 Example 2 was used in place of 1.5 Of of the 9(R)-(+)-acyloxycarboxylic acid dister used in Reference Example 1.
The same operation as in Reference Example 1 was performed except that (S)-(-)-acyloxycarboxylic acid ester 1,509 was used to obtain a colorless liquid of 670η (yield: 78%).

This product can be used for IR, NMR and MS except for the optical rotation shown below.
The analysis result of R2 in general formula (II) was in good agreement with the analysis result of butyrolactone obtained in Reference Example 1.
was confirmed to be (S)-(-)-butyrolactone in which is a methyl group.

(”]o' -25,10(C=4.O, CHaOH
) Examples 3 to 8 In the general formula (ill) used in Example 1, R1, R2 and R3 are each a methyl group, and the optical rotation of [α几'-+-a, as° (neat) RL, R2 and R
By performing the same operation as in Example 1, except that δ-ketocarboxylic acid ester in which 3 is a lower alkyl group shown in Table 1 and the product acyloxycarboxylic acid ester was not produced, the results shown in Table 1 were obtained. The results shown in 7C were obtained.

Table 1 below shows the results of 'H-NMR1IR and MS analysis of the acyloxycarboxylic acid ester product.

Acyloxycarboxylic acid S2'i'l-NMR obtained in Example 3: δPPmi,oo(3H,d,
J==7Hz, CHCHs).

1.11 (3H, t, J=7Hz, CH20)13
), 2.0 to 2.6 (5H, m, CH2CH3,C
H (J3. CH2C02CH3), 3.70 (3H
,s, 0CH3), 3.86(IH,dd, J
=11. H2tJ=6.4Hz, 0Cfiz), 4
．． 04 (IH, dd, J=11Hz.

J=5.6Hz, 0CR2) IR: 1735cWL-,' MS: 189 (M+13 Acyloxycarbo/acid ester obtained in Example 5 H-NMR: δpp" 0.95 (3H, t, J=
7Hz, CH2CH3).

0.99 (3H, d, J=7Hz, CHCHs)
, 1.72 (2H, m.

CH2CH3), 2.0-2.6 (5H, m, CH
2Cf(zCH3゜CHCHa, CH2C02CH3
), 3.68(3H,s, QCC84°3.88(
IH, dd, J=11Hz, J=6.4f(z,
0CH2).

4.06 (IH, dd, J=11Hz, J=5.6
Hz, QC! ! 2) IR: 1735c7n-' MS: 203 [M+11] Acyloxycarboxylic acid ester obtained in Example 7 H-NMR: 1.00 (3H, d, J=7Hz
, CHCH3), 1.18(6H,d, J=7H
z, CH(C1js)z), 2.0~2.9(4H
.

m, CH(CH3)2. CHCHs, CH2C0
2CH3), 3.69 (3H.

s, 0CR3), 3.90 (11-1, dd, J
= 11Hz, J = 6.4Hz.

OC! 112), 4.08 (IH2dd, 11H2,
J=5.6H2゜OCC20 IR:1735 Wound-1 MS103 (M+l) The analysis results of the acyloxycarboxylic acid esters obtained in Examples 4.6 and 8 are as in Example 3.
The results were almost consistent with the analysis results for the acyloxycarboxylic acid esters obtained in 5 and 7.

Reference Examples 3 to 8 Reference Example 1 except that the crude acyloxycarboxylic esters obtained in Examples 3 to 8 were used in place of the (R)-(+)-acyloxycarboxylic ester used in Reference Example 1. The same operation as above was performed, and the results shown in Table 2 were obtained. The NMRlIR and MS analysis results of the product, butyrolactone, were in good agreement with the analysis results of butyrolactone in Reference Example 1 (0').

Table 2 Example 91j9 35% hydrogen peroxide (0.7 rl) was added to methylene chloride (3 ml).
wtl, 5.6 at of trifluoroacetic anhydride was added dropwise to the resulting mixed solution while stirring under water cooling, and then 1 at room temperature.
, stirred for 5 hours to prepare a methylene chloride bath solution of trifluoroperacetic acid, and added to this solution the general formula ([[) where moiety and R3 are methyl groups, R2 is isopropyl M, and h
p, Ka((1, ID' + 5-45°(C=2.
(S) −(+)− with an optical rotation of 01 Hensen)
After a methylene chloride bath solution (5d) containing 900η of δ-ketocarboxylic acid ester was added dropwise under water cooling, 100 yxl of 0-saturated sodium bicarbonate solution stirred at room temperature for 15 hours was added and stirred well, and then the organic layer was separated. Water layer is methylene chloride 50d
Extracted three times. The organic layers were combined, washed successively with 100 tons of an aqueous solution of sodium thiothiosulfate and 100 tons of saturated brine, and then dried over anhydrous magnesium sulfate. By distilling off the solvent under reduced pressure, 870 cm of a yellow liquid was obtained. This liquid was subjected to silica gel column chromatography (using hexane/ethyl acetate=10/1 (g ratio) as a developing solution) to obtain 780 ml of colorless liquid (yield: 80 ml).

The following analysis results confirmed that this product was a (R)-(-)-acyloxycarboxylic acid ester of general formula (1) in which R1 and R3 were methyl groups and sR'' was an isopropyl group.

2.0~2.5(3H,m,Ctan2pCu)t3
．． 68 (3H, s.

0CH3), 3.97 (IH, dd, J=11.2
．． J=6.5Hz.

0Cf(z), 4.14(IH, dd, J=11
．． 2. J=5. lHz.

Oq Tomo 2) IR: 1735α-1 MS: 203 (M+1) (α) 21-4.1° (C= 4.8. CHcl!
3) Reference Example 9 600 μ of the (R)-(−)-acyloxycarboxylic acid ester obtained in Example 9 was dissolved in 5 vtl of methanol, and 140 μ of anhydrous potassium carbonate was added to this solution at 50° C. for 3.5 hours. Stirred. After cooling, 100 rxl of diethyl ether was added to the reaction mixture, and the insoluble matter formed was separated, and the p liquid was concentrated under reduced pressure to give 390 ml of yellow liquid.
I got it. This liquid was purified by silica gel column chromatography [hexane/ethyl acetate = 20/1 (volume ratio) was used as the developing solution], and 370 μg (96 μg) of colorless liquid was purified.
% yield) was obtained. According to the analysis results below, this product has general formula (II) in which R2 is an isopropyl group (R)
It was confirmed to be -(-)-butyrolactone.

'H-NMR: δpp'' 0.92 (3H, d, J=
6.6Hz, CHs).

0.95 (3H, d, J==6.9Hz, CHs
), 1.4-1.85 (LH.

m, CH), 1.9-2.8 (3Ht mt C
H2, CH), 3.8-4.1 (l H2mt CH
zO) + 4-3~4.6 (I HJ m, CH2
O) IR: 1775cvl-' MS: 128 (M") [α ear'-12,0' (C=1.6.Cα4) The optical rotation of (R)-(-) is according to the literature value [ α)2
3-12.3° (Cα4) (Au8t, J, C
hetn, 27.2293 (1974)).

Effects of the Invention According to the method of the present invention, optically active β-alkyl-γ-acyloxycarboxylic acid esters can be easily produced in good yields using easily obtained raw materials, as is clear from the above examples. can be manufactured. Further, according to the present invention,
As is clear from the above reference examples, it is possible to provide an optically active β-alkyl-γ-acyloxy carboxylic acid ester that can be derived into optically active β-alkyl-γ-butyrolactone in good yield.

Claims (1)

[Claims] 1. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^1, R^2 and R^3 are the same or different and each represents a lower alkyl group, represents an asymmetric carbon atom.) An optically active β-alkyl-γ-acyloxycarboxylic acid ester represented by: 2. General formulas ▲ Numerical formulas, chemical formulas, tables, etc. General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1 , R^2, R^3 and ^*C are as defined above.) A method for producing an optically active β-alkyl-γ-acyloxycarboxylic acid ester.