JPS63135371A - N-acyl lactams compound, production thereof and alcoholic fermentation accelerator containing said compound as active ingredient - Google Patents

Abstract

NEW MATERIAL:An N-acyl lactams compound expressed by formula I (n is 0, 1, 2 or 3). EXAMPLE:1-(2-Phenyl-2-hydroxyethanoyl)-2-piperidone. USE:An alcoholic fermentation accelerator having excellent unconventional fermentation accelerating effects on alcoholic fermentation. PREPARATION:A compound expressed by formula II is converted into an acid chloride, which is then subjected to coupling reaction with 2-piperidone or an alkylation product thereof to provide a compound expressed by formula III. The keto group of the resultant compound is then reduced and hydroxylated to afford the aimed compound expressed by formula I.

Description

Detailed Description of the Invention (Industrial Application Field) The present invention relates to N-acyllactam compounds represented by the general formula (1) (wherein n is 0.1.2 or 3) and The present invention relates to a method for producing the same and an alcohol fermentation promoter containing the same as an active ingredient.

(Prior Art) Alcohol fermentation has long been known for the production of alcoholic beverages such as sake, beer, and wine, but in recent years it has been applied to the production of energy-use alcohol as an alternative to petroleum as biotuel. Alcohol fermentation as bio-thuuel requires the use of inexpensive starchy raw materials and efficient fermentation from the perspective of producing alcohol for fuel.
The search for inexpensive raw materials and the development and research of various types of excellent yeast are underway.

On the other hand, as a method for efficiently carrying out fermentation, development is also being carried out in terms of fermentation techniques, in which yeast cells are immobilized and alcohol is continuously and efficiently produced. However, none of these methods has been able to improve fermentation efficiency to the point where it can be economically effective, and alcohol fermentation as a biotwinner is currently still at the research stage.

The present inventors first started research on physiologically active substances in plants, synthesized various compounds, and discovered that N-acyl lactam compounds are excellent as active substances (Japanese Patent Application Laid-Open No. 6-1133).
As a result of further research, it was discovered that only the novel N-acyllactam compound of the present invention having the specific structure described below has an excellent ability to promote fermentation in the alcoholic fermentation. The present invention was completed based on this knowledge.

(Means for Solving the Problems) That is, the present invention provides an N-acyllactam compound represented by the general formula (1) (where n is 0.1.2 or 3) and a method for producing the same. The present invention also relates to an alcohol fermentation promoter containing the same as an active ingredient.

Therefore, the N-acyllactam compound of the present invention is a novel compound and has an excellent fermentation promoting effect as an unprecedented alcohol fermentation promoter.

(for production) The present invention will be explained in detail below.

The novel compound of the present invention is an N-acyllactam compound represented by the general formula (+) (where n is 0.1.2 or 3), and examples of the compound include the following: . (Table 1) Table 1 Next, the manufacturing method of these compounds of the present invention will be explained.

The compound of the present invention represented by the general formula (1) (where n is 0.1.2 or 3) is represented by the general formula (II) (where n is 0.1.2 or 3). After acid chloridation of the compound represented by formula (III) (where n is 0.1.2 After obtaining a compound represented by (3) or 3), the keto group of this compound is reduced and hydroxylated.

First, from the compound represented by the general formula (II), the general formula (
The method for obtaining the compound represented by [11] is based on the general formula (II
It can be obtained by acid chloridizing the carboxyl group of the compound represented by > and then coupling reaction with an alkylamide of 2-piperidone or 2- and beryton.

For acid chloridation, thionyl chloride, phosphorus pentachloride, phosphorus trichloride, oxalyl chloride, etc. can be used, but it is preferable to use oxalyl chloride.

Further, in the coupling reaction, use of 2-piperidone or an alkylamide of 2-piperidone is selected as appropriate from the viewpoint of stability of the keto group and reaction yield depending on the type of compound represented by the general formula (II).

Incidentally, as the alkylamide of 2-piperidone, a trimethylsilylated product of 2-piperidone can be used.

The acid chloridation reaction and the coupling reaction can be carried out in the same reaction system, but from the viewpoint of reaction yield, it is necessary to select conditions under which the acid chloridation reaction is completely completed.

Furthermore, when carrying out these reactions, it is necessary to carry out the reactions at room temperature or a temperature lower than that in order to avoid the formation of by-products.

Next, the present invention provides general formula (III) obtained in this way
The keto group of the compound represented by is reduced and hydroxylated to obtain the compound represented by the general formula (1) of the present invention.

The compound represented by the general formula (m) is unstable to acids, alkalis, heat, etc., and cleavage of the acyl group and opening of the piperidone ring easily occur even in the presence of trace amounts of acids and alkalis. Commonly used reducing agents such as sodium borohydride, lithium aluminum hydride, which are metal hydrogen complex compounds, and alkylborane, which is an acidic reducing agent, cannot be used.

Therefore, in the present invention, the compound represented by the general formula (1) is produced by carrying out reduction by a catalytic reduction method under mild conditions using hydrogen gas as a reducing agent.

In addition, a catalyst is used at this time. Various reduction catalysts can be used as the catalyst, and although there are no particular limitations, reduction must be carried out under mild conditions. For example, in the case of a palladium-based catalyst, palladium-barium sulfate It is preferable to use

The compound of the present invention produced in this manner has an unprecedented and excellent fermentation promoting effect in alcoholic fermentation.

The compound of the present invention is generally used as an alcohol fermentation promoter by being added to a fermenter, but it may be added to the alcohol fermentation raw material or may be added alone to the tank during fermentation.

The accelerator may be added in a liquid form or as an oil as it is.

The proportion used varies depending on the type of yeast used for alcoholic fermentation, the raw materials used, the concentration of the fermentation liquid, etc.
The proportion used is not particularly limited, but is generally in the range of 0.00001 to 0.001 w% based on the amount of fermentation liquid.

(Examples) The present invention will be further explained below with reference to Examples, but the present invention is not limited thereto.

Moreover, all percentages indicate weight % unless otherwise specified.

Example 1 5.0 g of benzoyl formic acid was placed in a reaction flask equipped with a calcium chloride tube, and under stirring conditions dry tetrahydrofuran (hereinafter abbreviated as THF) lhl and 10 ml of dry benzene were added.
Then, to this was added oxalyl chloride 4.
8 g was added over about 15 minutes, followed by stirring for an additional 2 hours. After stirring, the inside of the flask was suctioned to remove THF, benzene, unreacted oxalyl chloride, and generated gas, and the reaction flask was placed in a water bath, and N-)samethylsilyl- dissolved in 1 hl of dry THF was added.
After 15.3 g of 2-piperidone was added dropwise, the reaction flask was taken out of the water bath and stirred at room temperature for 1 hour.

After stirring, add diethyl ether to the reaction flask,
After separating the ether layer, this ether solution was washed in the following order: 1N aqueous sodium hydroxide solution, 1N aqueous hydrochloric acid solution, saturated aqueous sodium chloride solution, and water. After dehydration with anhydrous sodium sulfate, the ether was distilled off to give a yellow color. An oil was obtained.

Next, this was subjected to silica gel column chromatography using a 7:3 mixed solvent of black form and hexane as an eluent to obtain pale yellow, oily compound 1-(hensoylformyl)-2.
- 4.5 g of 69 bottles was collected into 70 bottles.

Next, this was dissolved in ethyl acetate IQhl, 200 mg of 5% palladium-barium sulfate was added, and the mixture was stirred at room temperature under a hydrogen gas stream for 5 hours. After stirring, the mixture was filtered under suction, and the filtrate was washed with water and concentrated to obtain 3.7 g of a colorless, oily compound.

This compound was analyzed by mass spectrometry, elemental analysis, and IRlNMR.
From the following measurement results, which compounds are the compounds of the present invention?
'+Sietanoyl)-2-1 was confirmed to be 0 libin.

M S (EIMS), M+ 233 elemental analysis value C
66,22% 8 6.59% N 5.99% 0 21.2Q% I R(NEAT) 3350cm-'(-0H)
'H-NMR (90MHz, CDCh); δpp
m1.77 (4)1. l,) M-CH2-CILL
-Cdanee-)2.46 (2H,!11.)N-CO-
CJil-C)12-)3.73 (2)1,1.
〉N-CJiz-CH2-)6.15 (18,s,
Ph-C,ll0H-Co-)7.38 (5H,s
, Ph) Example 2 Malonic acid 1 was added to a reaction flask equipped with a calcium chloride tube.
0.4 g and 150 ml of dry benzene, and 22.2 g of triethanolamine was dried under stirring conditions at room temperature.
was dripped. After the malonic acid was dissolved, 22.7 g of trimethylsilyl chloride was gradually added using a dropping funnel, and stirring was continued at room temperature for 8 hours.

After the stirring was completed, the reaction solution was suction-filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was distilled under reduced pressure at 94 to 96°C to obtain 22.8 g of ditrimethylsilylmalonic acid.

15.03 g of this ditrimethylsilylmalonic acid was dissolved in 90 ml of dry diethyl ether, the flask was placed in a dry ice-ethanol bath, 3 qmi of a 16% hexane solution of butyllithium was added dropwise over about 20 minutes, and the mixture was further stirred for 15 minutes. After the stirring was completed, the flask was changed from a dry ice-ethanol bath to a water bath, and 4.20 g of benzoyl chloride dissolved in 9 ml of dry gel was added dropwise to the flask, and stirring was continued for 15 minutes.

An ice-cooled saturated aqueous sodium bicarbonate solution was added all at once and stirred vigorously for 10 minutes. Then, a dilute aqueous sulfuric acid solution was added little by little until the pH reached 1 to obtain a white Method'/R product. This was washed with water and then dried to obtain 4.5 g of 2-benzoyl acetic acid.

Next, 3.3 g of 2-benzoyl acetic acid was added to a reaction flask equipped with a calcium chloride tube, and 10 ml of dry THF and 10 ml of dry benzene were added and dissolved under stirring at room temperature. Add 4.8g of oxalyl chloride to this about 1
The mixture was added over a period of 5 minutes and stirred for an additional 2 hours. After stirring, the inside of the flask is suctioned to remove THF,
Remove benzene, unreacted oxalyl chloride, and evolved gas, place the reaction flask in a water bath, and dry THF 1.
A solution of 15.3 g of totrimethylsilyl-2-piperidone dissolved in 0++1 was added dropwise, and after the dropwise addition was completed, stirring was performed at room temperature for 1 hour.

After stirring, add diethyl ether, separate the ether layer, wash this ether solution in the following order: 1N aqueous sodium hydroxide solution, 1N aqueous hydrochloric acid solution, saturated aqueous sodium chloride solution, and water, and then dehydrate with anhydrous sodium sulfate. , the ether was distilled off to give a yellow oil.

Next, this was subjected to silica gel column chromatography using a mixed solvent of chloroform and hexane (7:3) as an eluent.A pale yellow, oily 1-(2-ethanoyl)-
2.7 g of 01J-9 was fractionated.

Next, this was dissolved in 100 ml of ethyl acetate, 200 mg of 5% palladium-barium sulfate was added, and the mixture was stirred at room temperature under a hydrogen gas stream for 5 hours. After stirring, the mixture was suction filtered, the filtrate was washed with water, and concentrated under reduced pressure to obtain a colorless,
2.2 g of oily compound was obtained.

This compound was analyzed by mass spectrometry, elemental analysis, and IRlNMR.
From the following measurement results, this compound is a compound of the present invention.
It was confirmed that it was 0 libin to 2-70.

M S (EIMS), M” 247 elemental analysis (I
LC68,51% H7,05% N 5.67% 0 1B, 77% IR (NEAT) 3350cI11-'(-0)
R' H-NMR (90MHz, CDCl s)
;δppm1.82 (4H, m, N-C
Ht-CJiz-CJtJx-CH2-)2.54 (
2H, m, )N-GO-C Mu CHe-)3.28
(2)1. d, -CHo)I-CJL, -Co-)3.
75 (2) 11m, N-C-1L2. -C
He-)5.19 (LH, t, Ph-IJIOH-C
H2-)7.33 (5H,S,Ph) Example 3 A reaction flask with a calcium chloride tube was placed in a water bath;
Add 3.6 g of 3-benzoylpropionic acid and dry under stirring conditions with 10 ml of THF and 10 ml of anhydrous benzene! +1 was added and dissolved. A solution of 10 g of 2-piperidone dissolved in 10 ml of a 1:1 mixed solution of dry THF and anhydrous benzene was added thereto, and 2.8 g of oxalyl chloride was added dropwise.The reaction flask was returned to room temperature from the water bath and stirring was continued for 3 hours. did.

After stirring, add diethyl ether, separate the ether layer, wash this ether solution in the following order: 1N aqueous sodium hydroxide solution, 1N aqueous hydrochloric acid solution, saturated aqueous sodium chloride solution, and water, and dehydrate with anhydrous sodium sulfate. After that, the ether was distilled off to obtain a yellow oil.Next, this was purified by silica gel column chromatography using a mixed solvent of 7:3 of chloroform and hexane as an eluent.
Next, this was dissolved in 50 ml of ethyl acetate, 5% palladium-barium sulfate 2001 was added, and the mixture was stirred at room temperature under a hydrogen gas stream for 3 hours. After stirring, the mixture was filtered under suction, and the filtrate was washed with water and concentrated under reduced pressure to obtain 2.1 g of a colorless, oily compound.

This compound was analyzed by mass spectrometry, elemental analysis, IR, and NMR.
From the following measurement results, this compound is a compound of the present invention.
It was confirmed that it was 7x7?9noyl)-2-pyheolivin.

M S (EIMS), M◆ 261 Elemental analysis value C 68.00% 8 7, 38% N 5.29% 0 19, 33% I R (NEAT) 3350 cm-'(-08)'
H-NMR (90MHz, CDCI,); δppm
1,88 (4H,11, 〉N-CHg-CJiz-
CJLz-)2, 16-2.29 (28,q, -C
HO)I-C,, L=-CHe-)2, 56-2.62
(4) 1,11,-Cl,-co-n<.

>N-CO-C-h-CHE-)
3,78 (2H,m,)N-CJiq-CH2-)5
, 50 (0 on LH, t, -C) 1-CH. -)7.
35 (5H, s, Ph) Example 4 A reaction flask with a calcium chloride tube was placed in a water bath.
Add 3.8 g of 4-benzoylvaleric acid, add and dissolve 10 ml of dry THF lhl and anhydrous benzene under stirring conditions, and then add 1:1 of dry THF and anhydrous benzene.
A solution of 2-piperidone 10 dissolved in 10 ml of a mixed solution of was added, 2.8 g of oxalyl chloride was added dropwise, the reaction flask was returned to room temperature from the water bath, and stirring was continued for 3 hours.

After stirring, add diethyl ether, separate the ether layer, and add this ether solution to a 1N aqueous sodium hydroxide solution,
The mixture was washed successively with a 1N aqueous hydrochloric acid solution, a saturated aqueous sodium chloride solution, and water, dried over anhydrous sodium sulfate, and the ether was distilled off to obtain a yellow oil.

Next, this was subjected to silica gel column chromatography using a mixed solvent of chloroform and hexane (7:3) as the flit solution.
li 1-(4-to1 ndaryl7'tanoyl)-2-hi0
2.4 g of helivin was collected.

This was dissolved in 50 ml of ethyl acetate, and 5% palladium-
Barium sulfate 200B was added and stirred for 3 hours at room temperature under a hydrogen gas flow. After stirring, the mixture was filtered under suction, and the filtrate was washed with water and concentrated under reduced pressure to obtain 169 g of a colorless, oily compound.

This compound was analyzed by mass spectrometry, elemental analysis, and IRlNMR.
From the measurement results below, this compound is a compound of the present invention.
It was confirmed that it was 0 libin to 6-2-1.

M S (EIMS), M◆ 275 Elemental analysis value C71,33% 8 7.82% N 5.10% 0 15.75% IR (NEAτ) 3350cm-'(-0)1)'
H-NMR(90MH2,C:DCI9); δp
pI111.7-2.2 (8)1. m, nN
-CH, -Cut+, -CJLL-.

-C) 108-CmuCJLL-') 2-4~2-7 C4H#, -CJLz-CO-N-C
O-CJJz-)3.70 (2H, m, N-N-
CJiz-CHa-)5.33 (1)1. t, -〇upper 0H-GHQ-) 7.35 (5H, s, Ph) Example 5 500 ml of an aqueous solution (liquid pH 5.0) containing 10% sig sugar and 0.05% ammonium sulfate was placed in a 1 L Erlenmeyer flask.
The mixture was then sterilized at 120°C for 15 minutes and used as a fermentation substrate.

Commercially available baker's yeast (manufactured by Furifuta 3 Yeast Co., Ltd., raw yeast)
was used as a seedling, and after suspending yeast in a 5-fold dilution of the fermentation substrate, it was allowed to stand at 25°C for 1 hour.

Compounds of the invention shown in Table 1 and for comparison 1
-(3-Phenyl7°UlPinoy3)-2-1 and 0livin were each dissolved in ethanol to prepare a II#h% solution and use it as a sample solution.

3.5x1 yeast suspension for 500a+1 fermentation substrate
The cells were inoculated at a rate of 0'cells/ml, left to stand at 30°C for 1 hour, and then 0.5ml of each sample solution was added.
Static fermentation was performed at °C.

A predetermined amount of liquid was collected from each fermentation flask at predetermined intervals from the start of fermentation, and the ethanol concentration of the fermentation liquid was measured by gas chromatography.

The results are shown in Table 2.

Table 2

Claims (3)

[Claims] (1) General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (However, in the formula, n is 0, 1, 2, or 3) N-acyllactam compounds. (2) General formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) (However, in the formula, n is 0, 1, 2 or 3) After acid chloridation of the compound, 2 -By coupling reaction with piperidone or alkylated product of 2-piperidone, general formula (III) ▲Mathematical formula, chemical formula, table, etc.▼(III) (However, n in the formula is 0, 1, 2, or 3. ) After obtaining the compound represented by formula (I), the keto group of this compound is reduced and hydroxylated. n is 0, 1, 2 or 3). (3) General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (However, in the formula, n is 0, 1, 2 or 3) An N-acyllactam compound as an active ingredient Alcohol fermentation accelerator.