JPH0747562B2 - 2-Methyleneglutaric acid 1-monoester and process for producing the same - Google Patents

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to 2-methyleneglutaric acid 1-monoester, which is expected to be used as a polymer monomer and a synthetic intermediate, and a process for producing the same.

[0002]

2. Description of the Related Art Regarding 2-methyleneglutaric acid diester, there are several patents [US Pat. No. 3,074,999].
No. 4, Japanese Patent Publication No. 41-19331, Japanese Patent Publication No. 42-11
047, British Patent 1,100,350, Japanese Patent Publication No. 45-29646] and the literature [E. R. Buc
hman, A .; O. Reims, M .; J. Schlat
ter, Jour. Am. Chem. Soc. , 64 ,
2705 (1942); M. Baizer, J .;
D. Anderson, Jour. Org. Che
m. , 30 , 1357 (1965)] are known,
Regarding 2-methylene glutaric acid, the above-mentioned E. R.
The description can be found in the work of Buchman et al. However, monoesters of 2-methyleneglutaric acid (1-monoester and 5-monoester), which are considered to be useful as high molecular weight monomers like 2-methyleneglutaric acid and its diesters and as synthetic intermediates, have been conventionally used. Not listed in the technical data.

In view of the above circumstances, there has been a demand for a method for efficiently producing high-purity 2-methyleneglutaric acid monoesters.

[0004]

The object of the present invention is to provide 2-methyleneglutaric acid 1 represented by the general formula [I] among two monoesters of 2-methyleneglutaric acid.
-To provide a monoester and a method for producing it simply and efficiently.

[0005]

Means and Actions for Solving the Problems As a result of earnest studies to achieve the above object, the present inventor found that a lipase acts on a diester represented by the general formula [II] having a corresponding alkyl group. It was found that 1-monoester represented by the general formula [I] can be obtained in a high yield by hydrolyzing the 5-position ester bond regioselectively depending on the type of lipase, and completed the present invention. .

That is, the first aspect of the present invention is the general formula [I]

[0007]

[Chemical 3] (In the formula, R represents an alkyl group having 1 to 4 carbon atoms) and is 2-methyleneglutaric acid 1-monoester.

The second aspect of the present invention is the general formula [II]

[0009]

[Chemical 4] (Wherein R has the same meaning as in the case of the above formula [I]), and a lipase having the ability to regioselectively hydrolyze the 5-position ester bond of 2-methyleneglutaric acid diester It is used for hydrolysis to obtain 2-methyleneglutaric acid 1-monoester represented by the general formula [I], which is a method for producing the monoester.

In parallel with the present invention, an attempt was made to hydrolyze the diester using an acid or alkali, but it is difficult to stop the reaction at the monoester stage, and both ester bonds are hydrolyzed sequentially. Since it was decomposed, the yield was low, and the regioselectivity of the monoester was not observed.

The present invention will be specifically described below.

The compound of the formula [II] used as a raw material in the present invention has a corresponding alkyl group, in accordance with, for example, US Pat. No. 3,074,999, using an organic phosphorus compound such as tri-n-butylphosphine as a catalyst. By carrying out the dimerization reaction of the acrylic acid ester which it has, it can be easily manufactured in high yield. R in the formula [II] represents an alkyl group, particularly preferably an alkyl group having 1 to 4 carbon atoms, and examples thereof include methyl, ethyl, n-propyl, isopropyl and n-butyl.

As the lipase used in the present invention, the 5-position ester bond of 2-methyleneglutaric acid diester represented by the general formula [II] is regioselectively hydrolyzed,
A lipase extracted from porcine pancreas, Rhizo, may be used as long as it gives 1-monoester represented by the general formula [I], regardless of origin or type such as animal, plant, microorganism, etc.
filamentous fungus of genus pus, yeast of genus Candida, Alcali
genes, Chromobacterium, Pse
A lipase produced by a microorganism such as a bacterium of the udomonas genus is used. More specifically, Porci
ne Pancreas Lipase (Sigma
Manufactured by Rhizopus delemar Lipase D
(Manufactured by Amano Pharmaceutical Co., Ltd.), Candida cylindrac
ea lipase OF, MY (manufactured by Meito Sangyo), Alca
Ligenes sp lipase PL (manufactured by Meito Sangyo),
Chromobacterium viscosum lipase LP (manufactured by Asahi Kasei), Pseudomonas
Commercially available enzymes such as sp lipase PS (manufactured by Amano Pharmaceutical Co., Ltd.) can be mentioned.

In the present invention, when lipase is allowed to act on the substrate diester, the reaction is carried out in a liquid medium, and the reaction medium is an aqueous medium such as a buffer solution containing ion-exchanged water or phosphate, In addition, tertiary butanol, acetone, tetrahydrofuran, n-hexane, n
Organic solvents such as heptane, isooctane, benzene, and toluene can be used regardless of the type as long as they do not inhibit the activity of lipase. Further, a culture solution of a microorganism containing the enzyme or an extract of animal and plant tissues can also be used. Further, the enzyme may be used alone or may be immobilized and used.

The pH of the reaction solution is preferably in the range of 4-10, more preferably 6-8. When the pH is lowered as the hydrolysis reaction proceeds, it is preferable to add a base such as sodium hydroxide, potassium hydroxide or ammonia to maintain the above pH range during the reaction. If necessary, a surfactant may be added to disperse the substrate in the reaction medium. The amount of the diester charged into the reaction medium is not particularly limited, but it is generally 0.1 to 1,000 g, preferably 1 to 100 g per liter of the reaction medium. At this time, the diester may be added all at once at the beginning of the reaction, but may be added batchwise or continuously. The addition amount of the enzyme to be used is determined depending on the activity of the enzyme, but in the case of general commercial lipase, it is 0.1 to 1,000 g, preferably 1.0 to 1 per mol of the diester of the substrate.
It is 100 g. The reaction temperature is 20 to 50 ° C, preferably 25 to 35 ° C. The above conditions are appropriately selected so that the reaction is completed within 48 hours.

The reaction may be carried out while stirring the solution or suspension of the substrate, or may be carried out by circulating the reaction medium through a column packed with the immobilized enzyme or microorganism. The reaction product can be easily separated from the reaction solution by solvent extraction or the like. For example, when the reaction is carried out in an aqueous reaction medium, the pH of the reaction solution is first adjusted to 7, and unreacted diester is extracted and removed using a solvent such as ethyl acetate, ethyl ether, methyl isobutyl ketone. Then, the 2-methyleneglutaric acid 1-monoester produced by lowering the pH to 4 or less can be extracted, and the solvent can be distilled off, followed by purification by vacuum distillation or a recrystallization method.

[0017]

The present invention will be described in more detail with reference to the following examples.

Example 1 2-Methylene glutaric acid 1-
Synthesis of monoethyl ester 2-methylene glutaric acid diethyl ester 20.0 g
And lipase OF (Meito Sangyo Co., Ltd., 5.0 g) were added to M / 10 phosphate buffer, pH 7.5, 200 ml, and added at 28 ° C. for 15
The reaction was carried out while stirring with a magnetic stirrer for hours. After the reaction was completed, 10% aqueous sodium carbonate solution was added to the reaction solution to adjust the pH to 7.0, and ethyl acetate 200
Unreacted diester was removed by extraction with ml three times. Then add concentrated sulfuric acid to the aqueous layer to lower the pH to 2.0,
Extraction was performed again with ethyl acetate. Extract with ethyl acetate 2
This was repeated 3 times with 100 ml each, and the organic layers were combined, dried over sodium sulfate overnight, and the ethyl acetate was distilled off.
2 g were obtained. The residue was vacuum distilled to purify 2-methyleneglutaric acid 1-monoethyl ester. A fraction having a boiling point of 93 to 96 ° C./1 mmHg was collected. The yield was 11.4 g, and the yield was 73.5%.

The ¹ H-NMR, IR and GLC analysis values of this fraction are as follows.

¹ H-NMR (CDCl ₃ ): δ (p
pm) = 1.31 (3H, t, J = 14.3Hz),
2.63 (4H, s), 4.19 (2H, q), 5.6
5 (1H, s), 6.24 (1H, s), 10.76
(1H, s) IR (KBr liquid film): 1140, 1270, 163
0, 1715, 2940, 2980 cm ^-1 GLC [Column: AdvanceDS (2 m) with SHINCARBON A as a support, temperature 180 ° C]:
2-Methyleneglutaric acid 1-monoethyl ester (Rt17.6 min): 2-methyleneglutaric acid 5
-Monoethyl ester (Rt20.6min) = 98:
2 Example 2 Synthesis of 2-methylene glutaric acid 1-monomethyl ester 17.2 g of 2-methylene glutaric acid dimethyl ester
And 4.0 g of lipase OF (manufactured by Meito Sangyo Co., Ltd.) were dissolved in 150 ml of M / 10 phosphate buffer pH 7.5, 28 ° C for 15
The reaction was carried out while stirring with a magnetic stirrer for hours. After completion of the reaction, the reaction solution was treated in the same manner as in Example 1 to dehydrate the ethyl acetate extract of the pH 2 aqueous layer, and then the ethyl acetate was distilled off to obtain 10.0 g of a residue. This was a crystal of 2-methyleneglutaric acid 1-monomethyl ester (yield 68.4%). The crude crystals were dissolved in ethyl acetate and recrystallized to obtain crystals having a melting point of 55 to 56 ° C. The instrumental analysis results were as follows.

¹ H-NMR (CDCl ₃ ): δ (p
pm) = 2.63 (4H, s), 3.79 (3H,
s), 5.66 (1H, s), 6.24 (1H, s),
10.55 (1H, s) IR (KBr tablet): 1150, 1270, 163
5, 1690, 1720, 2960, 3020 cm ⁻¹ GLC (analytical conditions are the same as in Example 1): 2-Methyleneglutaric acid 1-monomethyl ester (Rt17.2)
min): 2-methylene glutaric acid 5-monomethyl ester (Rt 19.2 min) = 100: 0 Example 3 Synthesis of 2-methylene glutaric acid 1-mono-n-butyl ester 2-methylene glutaric acid di-n -Butyl ester 2
M / of 6.3 g and 4.0 g of lipase OF (manufactured by Meito Sangyo)
10 phosphate buffer pH 7.5, added to 150 ml, 28
The reaction was performed while stirring with a magnetic stirrer at 19 ° C. for 19 hours. The reaction solution was treated in the same manner as in Example 1 to obtain 8.4 g of a residue. This is mainly composed of 2-methylene glutaric acid 1-monobutyl ester 2-
It was a methylene glutaric acid monoester (yield 4
2.0%). The instrumental analysis results were as follows.

¹ H-NMR (CDCl ₃ ): δ (p
pm) = 0.94 (3H, d), 1.13 to 1.77.
(4H, m), 2.63 (4H, s), 4.18 (2
H, q, J = 20.0 Hz), 5.64 (1H, s),
6.24 (1H, s), 9.91 (1H, s) IR (KBr liquid film): 1140, 1280, 163
0, 1715, 2930, 2955 cm ^-1 GLC (analytical conditions are the same as in Example 1): 2-methyleneglutaric acid 1-mono-n-butyl ester: 2-methyleneglutaric acid 5-mono-n-butyl ester = 7
7:33 Examples 4 to 13 Synthesis of 2-methyleneglutaric acid 1-monoethyl ester from 2-methyleneglutaric acid diethyl ester by various lipases 50 mg of 2-methyleneglutaric acid diethyl ester and the lipases listed in Table 1 below. 10mg of 1 kind in M / 1
0 in phosphate buffer pH 7.5, 1 ml in a test tube,
The reaction was carried out with shaking at 28 ° C. for 15 hours. After the reaction was completed, 2N sulfuric acid was added to the reaction solution to lower the pH to 2.0,
After extraction with 1 ml of ethyl acetate and gas chromatography of the organic layer, unreacted diester and 1-monoester produced by enzymatic hydrolysis and 5
-The composition ratio of the monoester was examined. The results are shown in Table 1.
It was as shown in. By the way, the diester was not decomposed at all in the enzyme-free reaction described in Reference Example.

[0023]

[Table 1] In addition, when the ethyl acetate extract was dehydrated with sodium sulfate, ethyl acetate was distilled off and HPLC analysis was carried out under the following conditions. As a result, 2-methyleneglutaric acid was produced when any of the enzymes shown in Table 1 was used. I didn't.

HPLC analysis conditions Pre-column: SHODEX SUGAR SH-101
1P 6 mmφ × 50 mm column: SHODEX SUGAR SH-101
18 mmφ × 300 mm Column temperature: 50 ° C. Effluent: N / 100 H ₂ SO ₄ flow rate: 0.5 ml / min Detection: R1 detector Example 14 Reaction in organic solvent 2-Methyleneglutaric acid dimethyl ester 172 m
g, lipase OF 40 mg, water 30 mg, NaHCO ₃
84 mg was added to 3 ml of tertiary butanol in a test tube, and the reaction was carried out at 27 ° C. for 6 hours while shaking. After the reaction was completed, the filtrate obtained by filtering the reaction solution with filter paper was subjected to GLC analysis under the same conditions as in Example 4. As a result, unreacted diester 91%, 1-monoester 9%, 5-monoester 0 It was a composition of%.

[0025]

INDUSTRIAL APPLICABILITY The 2-methyleneglutaric acid 1-monoester according to the present invention and the process for producing the 2-methyleneglutaric acid 1-monoester useful as a polymer monomer or a synthetic intermediate are newly put to practical use. It is possible to provide a high-purity monoester with a high yield by having the effect that it can be provided at a level, and by causing lipase to act on 2-methyleneglutaric acid diester to hydrolyze the 5-position ester bond regioselectively. The effect of being played is also played.

Claims (2)

[Claims] 1. 2-Methyleneglutaric acid 1-monoester represented by the general formula [I]. [Chemical 1] (However, R is an alkyl group having 1 to 4 carbon atoms) 2. A compound represented by the general formula [II]: (Wherein R is an alkyl group having 1 to 4 carbon atoms), 2-methyleneglutar is obtained by using a lipase having the ability to regioselectively hydrolyze the 5-position ester bond of 2-methyleneglutaric acid diester. A method for producing 2-methyleneglutaric acid 1-monoester represented by the general formula [I] according to claim 1, wherein the 5-position ester bond of the acid diester is hydrolyzed.