JPH05255192A - Production of beta,gamma-unsaturated alpha-keto ester - Google Patents

Abstract

PURPOSE:To obtain the subject compound useful as a synthetic intermediate for pharmaceuticals, agricultural chemicals, etc., from an inexpensive raw material using a simple reaction operation by treating a specific gamma-alkoxy-alpha-keto ester with an acid catalyst or a base catalyst to eliminate an alcohol from the ester. CONSTITUTION:The objective beta,gamma-unsaturated alpha-keto ester of formula II (e.g. 2-oxo-4-phenyl-3-butenoic acid ethyl ester) is produced by dissolving a gamma-alkoxy-alpha- keto ester of formula I (R<1> is alkyl, aryl, vinyl or heterocyclic compound residue; R<2> and R<3> are lower alkyl) (e.g. 4-methoxy-2-oxo-4-phenylbutanoic acid ethyl ester) in a solvent such as benzene, adding an acid catalyst (e.g. silica gel) or a base catalyst to the solution, reacting for 1hr under heating to eliminate an alcohol, leaving the reaction product to cool, filtering to separate the catalyst and purifying the filtrate by silica gel chromatography.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a process for producing β, γ-unsaturated α-ketoesters useful as synthetic intermediates for pharmaceuticals and agricultural chemicals.

[0002]

2. Description of the Related Art A method for synthesizing β, γ-unsaturated α-ketoesters has long been known as a base catalyzed condensation method of aromatic aldehydes and pyruvic acid [J. Am. Chem. Soc.
47 page] is known, but this method has a drawback in that a substituent other than aromatic cannot be introduced as a substituent at the γ-position. In recent years, methods using Grignard reagents [S
ynthesis, 1988, 564 pages] and the method using Wittig reaction
[CRAcad.Sc.Paris, Serie C, 1970, 270 volumes, 1312 pages] has been developed.

[0003]

However, in the method using the Grignard reagent, the available Grignard reagent is limited, and in the method by the Wittig reaction, relatively expensive 3-bromopyruvic acid must be used as a raw material. However, it is not always an industrially advantageous method.

It is an object of the present invention to provide a method for producing a β, γ-unsaturated α-ketoester starting from an inexpensive raw material by a simple reaction operation.

[0005]

The present inventors have found that γ-alkoxy-α-obtained by a well-known method [JP-A-1-79140].
As a result of repeated studies to develop a method for converting an alcohol from a ketoester to β-γ-unsaturated α-ketoester by β-eliminating the alcohol,
¹ represents an alkyl group, an aryl group, a vinyl group or a heterocyclic compound, and R ² and R ³ represent a lower alkyl group. It was found that β, γ-unsaturated α-ketoesters can be obtained in good yield by using silica gel for chromatography as a catalyst in the reaction step of 1), and completed the present invention.

[Chemical 3]

That is, the present invention is characterized by using silica gel for chromatography as an acid catalyst when eliminating the alcohol of the γ-alkoxy-α-keto ester represented by the general formula [1]. 2] relates to a method for producing a β, γ-unsaturated α-ketoester.

The present invention will be described in detail below. The γ-alkoxy-α-ketoester, which is the starting compound in the method of the present invention, is represented by the general formula [1].
Specific examples of ¹ include alkyl groups such as isopropyl, heptyl and phenethyl, aryl groups such as phenyl, 4-methoxyphenyl and 4-chlorophenyl, vinyl groups such as styryl, and heterocyclic compounds such as 2-thienyl and 2-furyl. Etc. can be mentioned. Specific examples of R ² and R ³ are lower alkyl groups such as methyl, ethyl, propyl and butyl.

The catalyst used for the elimination of alcohol is preferably silica gel for chromatography, and the amount used is not particularly limited, but 100 to 500 g is used per 1 mol in the compound of the general formula [1].

The reaction is carried out using a hydrocarbon solvent such as benzene and toluene at a reaction temperature of 50 to 110 ° C.
It is preferably 80 ° C.

In the present invention, as described above, the γ-alkoxy-α-ketoester represented by the general formula [1] is used as a raw material as shown in the reaction formula of Chemical formula 3, but γ- By combining with a well-known method for producing an alkoxy-α-ketoester, a β, γ-unsaturated α-ketoester can be produced more efficiently. That is, in Chemical formula 4, R ¹ represents an alkyl group, an aryl group, a vinyl group, or a heterocyclic compound, and R ² ,
R ³ represents a lower alkyl group. ), The acetal of the general formula [3] and the 2- (trimethylsiloxy) acrylic acid ester of the general formula [4] are reacted with boron trifluoride etherate as an activator to produce a crude product of the general formula [1]. The product is obtained and treated with silica gel for chromatography to produce a β, γ-unsaturated α-keto ester of the general formula [2].

[Chemical 4]

[0011]

EXAMPLES The present invention will be described below with reference to examples.
The NMR spectrum was measured using FA-90A or EX-400 manufactured by JEOL. The infrared absorption spectrum was measured using JASCO Corporation A-102.

[0012]

Example 1 Preparation of ethyl 2-oxo-4-phenyl-3-butenoate

2.76 g (11.7 mmol) of ethyl 4-methoxy-2-oxo-4-phenylbutanoate was dissolved in 250 ml of benzene, 10 g of silica gel for chromatography was added, and the mixture was heated under reflux for 1 hour. After allowing to cool, silica gel is filtered and isolated and produced by silica gel column chromatography (hexane: ethyl acetate = 9: 1) to obtain 2.19 g (yield 92%) of the title compound. ¹ H NMR,
The structure was confirmed by IR. The data is shown below.

¹ HNMR (CDCl ₃ ): δ = 1.41 (t, 3)
H, J = 7Hz), 4.40 (q, 2H, J = 7Hz), 7.36 (d, 1H, J = 16H
z), 7.40-7.47 (m, 3H), 7.63 (dd, 2H, J = 2, 5Hz), 7.86
(d, 1H, J = 16Hz). IR (neat) (cm ^-1 ): 3000,
1725, 1690, 1665, 1600, 1575, 1450, 1320, 1300, 1
255, 1140, 1080, 980, 740, 685.

[0015]

Example 2 Preparation of ethyl 2-oxo-4-phenyl-3-butenoate (method starting from acetal)

Under an argon atmosphere, 1.84 g (12 mmol) of benzaldehyde dimethyl acetal and 2.73 g (1 of ethyl 2- (trimethylsiloxy) acrylate) were used.
4.5 mmol of dry dichloromethane solution (80 m
1) is cooled to −78 ° C., and 1.87 g (13.2 mmol) of boron trifluoride etherate is added dropwise. The reaction temperature is gradually raised to 0 ° C. and the mixture is stirred at 0 ° C. for 2 hours. A saturated aqueous sodium hydrogencarbonate solution is added to neutralize and the temperature is returned to room temperature. Extract with dichloromethane and dry the extract over anhydrous magnesium sulfate. The crude product of ethyl 4-methoxy-2-oxo-4-phenylbutanoate obtained by filtration and concentration is dissolved in 140 ml of benzene, 5 g of silica gel for chromatography is added, and the mixture is heated under reflux for 1 hour. After allowing to cool, the silica gel is filtered and isolated and produced by silica gel column chromatography (hexane: ethyl acetate = 9: 1) to obtain 2.29 g (yield 93%) of the title compound. ¹ H
The structure was confirmed by NMR and IR.

¹ H NMR and IR data are the same as those described in Example 1.

[0018]

Example 3 Preparation of ethyl 4- (4-methoxyphenyl) -2-oxo-3-butenoate

By using 4-methoxybenzaldehyde dimethyl acetal instead of benzaldehyde dimethyl acetal in the above Example 2 and carrying out the same reaction, the title compound could be obtained with a yield of 83%. Melting point 4
9-51 ° C. ^The structure was confirmed by ¹ HNMR and IR.
The data is shown below.

¹ HNMR (CDCl ₃ ): δ = 1.41 (t, 3
H, J = 7Hz), 3.86 (s, 3H), 4.39 (q, 2H, J = 7Hz), 6.93
(d, 2H, J = 9Hz), 7.24 (d, 1H, J = 16Hz), 7.59 (d, 2H, J
= 9Hz), 7.83 (d, 1H, J = 16Hz). IR (KCl) (c
m ^-1 ): 2998, 1720, 1680, 1590, 1570, 1515, 1250,
1170, 1070, 1030, 1000, 825, 780, 710.

[0021]

Example 4 Preparation of ethyl 4- (4-chlorophenyl) -2-oxo-3-butenoate

By substituting 4-chlorobenzaldehyde dimethyl acetal for benzaldehyde dimethyl acetal in Example 2 and carrying out the same reaction, the title compound could be obtained in a yield of 89%. Melting point 77
-79 ° C. ^The structure was confirmed by ¹ HNMR and IR. The data is shown below.

¹ HNMR (CDCl ₃ ): δ = 1.42 (t, 3)
H, J = 7Hz), 4.40 (q, 2H, J = 7Hz), 7.35 (d, 1H, J = 16H
z), 7.40 (d, 2H, J = 9Hz), 7.57 (d, 2H, J = 9Hz), 7.81
(d, 1H, J = 16Hz). IR (KCl) (cm ^-1 ): 300,
1715, 1685, 1585, 1565, 1250, 1070, 995, 830, 780,
750.

[0024]

Example 5 Preparation of ethyl 2-oxo-6-phenyl-3,5-hexadienoate

Cinnamaldehyde dimethyl acetal was used in place of the benzaldehyde dimethyl acetal of Example 2 and the same reaction was carried out to obtain the title compound in a yield of 77%. Melting point ° C. ¹ HNM
The structure was confirmed by R and IR. The data is shown below.

¹ HNMR (CDCl ₃ ): δ = 1.40 (t, 3
H, J = 7Hz), 4.37 (q, 2H, J = 7Hz), 6.89 (d, 1H, J = 15H
z), 6.98 (dd, 1H, J = 111,15Hz), 7.09 (d, 1H, J = 15Hz),
7.33-7.41 (m, 3H), 7.51 (dd, 2H, J = 2,8Hz), 7.65 (dd,
1H, J = 111,15Hz). IR (KCl) (cm ^-1 ): 3000,
1715, 1675, 1570, 1270, 1210, 1065, 1015, 765, 74
5,680.

[0027]

Example 6 Preparation of ethyl 2-oxo-4- (2-thienyl) -3-butenoate

By using 2-thiophene aldehyde dimethyl acetal instead of benzaldehyde dimethyl acetal in the above Example 2 and carrying out the same reaction, the title compound could be obtained in a yield of 86%. Melting point 44-
47 ° C. ^The structure was confirmed by ¹ HNMR and IR. The data is shown below.

¹ HNMR (CDCl ₃ ): δ = 1.41 (t, 3)
H, J = 7Hz), 4.39 (q, 2H, J = 7Hz), 7.12 (dd, 1H, J = 3,5H
z), 7.16 (d, 1H, J = 16Hz), 7.42 (d, 1H, J = 3Hz), 7.52
(d, 1H, J = 5Hz), 7.99 (d, 1H, J = 16Hz). IR (KC
l) (cm ^-1 ): 3000, 1700, 1680, 1590, 1250, 122
5, 1190, 1080, 1040, 970, 855, 775, 715, 705.

[0030]

Example 7 Preparation of ethyl 4- (2-furyl) -2-oxo-3-butenoate

Furfural dimethyl acetal was used in place of the benzaldehyde dimethyl acetal of the above Example 2 and the same reaction was performed to obtain the title compound in a yield of 19%. Melting point 48-49.5 [deg.] C.
^The structure was confirmed by ¹ HNMR and IR. The data is shown below.

¹ HNMR (CDCl ₃ ): δ = 1.41 (t, 3
H, J = 7Hz), 4.38 (q, 2H, J = 7Hz), 6.56 (dd, 1H, J = 1.8,
2.3Hz), 6.84 (d, 1H, J = 2.3Hz), 7.20 (d, 1H, J = 16Hz),
7.59 (d, 1H, 1.8Hz), 7.64 (d, 1H, J = 16Hz). IR
(KCl) (cm ^-1 ): 3430, 3160, 3130, 3050, 300
0, 1720, 1680, 1600, 1550, 1475, 1255, 1200, 1090,
1070, 1020, 985, 750, 675.

[0033]

Example 8 Preparation of ethyl 2-oxo-6-phenyl-3-hexenoate

By using 3-phenylpropionaldehyde dimethyl acetal in place of the benzaldehyde dimethyl acetal of Example 2 and performing the same reaction, the title compound could be obtained in a yield of 57%. ¹
The structure was confirmed by HNMR and IR. The data is shown below.

¹ HNMR (CDCl ₃ ): δ = 1.36 (t, 3
H, J = 7Hz), 2.45-2.93 (m, 4H), 4.32 (q, 2H, J = 7Hz),
6.63 (d, 1H, J = 16Hz), 7.05-7.42 (m, 6H).

[0036]

Example 9 Preparation of ethyl 5-methyl-2-oxo-3-hexenoate

By using isopropylaldehyde dimethyl acetal instead of benzaldehyde dimethyl acetal in the above Example 2 and carrying out the same reaction, the title compound could be obtained in a yield of 58%. ¹ H NMR,
The structure was confirmed by IR. The data is shown below.

¹ HNMR (CDCl ₃ ): δ = 1.12 (d, 6)
H, J = 6Hz), 1.37-1.43 (m, 2H), 1.39 (t, 3H, J = 7Hz),
2.53-2.61 (m, 1H), 4.36 (q, 2H, J = 7Hz), 6.61 (dd, 1H,
J = 2,16Hz), 7.16 (dd, 1H, J = 7, 16Hz). IR (nea
t) (cm ^-1 ): 3450, 2970,1730, 1700, 1675, 162
5, 1470, 1370, 1310, 1250, 1170, 1150, 1080, 1010,
985.

[0039]

Example 10 Preparation of ethyl 2-oxo-3-undecenoate

By using octanal dimethyl acetal instead of benzaldehyde dimethyl acetal in the above Example 2 and carrying out the same reaction, the title compound could be obtained in a yield of 69%. ^The structure was confirmed by ¹ HNMR and IR. The data is shown below.

¹ HNMR (CDCl ₃ ): δ = 0.88 (t, 3
H, J = 5Hz), 1.31-1.47 (m, 19H), 2.32 (q, 2H, J = 6Hz),
4.35 (q, 2H, J = 7Hz), 6.64 (d, 1H, J = 16Hz), 7.21 (dt,
1H, J = 6, 16Hz). IR (neat) (cm ^-1 ): 345
0, 2930, 2850, 1730, 1700, 1675, 1620, 1460, 1370,
1300, 1250, 1175, 1150, 1090, 1010, 980.

[0042]

Example 11 Preparation of ethyl 2-oxo-4-phenyl-3-butenoate

Ethyl 4-methoxy-2-oxo-4-phenylbutanoate (253 mg, 1.1 mmol) was dissolved in benzene (10 ml) to prepare p-toluenesulfonic acid (204 m).
g and heated under reflux for 1 hour. After allowing to cool, a saturated aqueous sodium hydrogen carbonate solution is added to neutralize, and the mixture is extracted with ether.
After drying over anhydrous magnesium sulfate, the solvent was removed and the product was isolated and produced by silica gel column chromatography (hexane: ethyl acetate = 9: 1) to give 76 mg of the title compound (yield 3
5%). ^The structure was confirmed by ¹ HNMR and IR. Data are the same as described in Example 1.

[0044]

Example 12 Preparation of ethyl 2-oxo-4-phenyl-3-butenoate

104 mg (0.44 mmol) of ethyl 4-methoxy-2-oxo-4-phenylbutanoate is dissolved in 10 ml of ethanol, 47 mg of sodium carbonate is added, and the mixture is stirred at room temperature for 2 hours. Aqueous ammonium chloride solution is added for neutralization, ethanol is removed, and the mixture is extracted with ether.
After drying over anhydrous magnesium sulfate, the solvent was removed, and the product was isolated and produced by silica gel column chromatography (hexane: ethyl acetate = 9: 1), and 12 mg of the title compound (yield 1
3%). ^The structure was confirmed by ¹ HNMR and IR. Data are the same as described in Example 1.

[0046]

Example 13 Preparation of ethyl 2-oxo-4-phenyl-3-butenoate

103 mg (0.44 mmol) of ethyl 4-methoxy-2-oxo-4-phenylbutanoate was dissolved in 10 ml of tetrahydrofuran to obtain 18 m of lithium chloride.
g and 0.06 ml of triethylamine are added, and the mixture is stirred at room temperature for 4 hours. Add water and extract with ether. After drying over anhydrous magnesium sulfate, the solvent was removed and silica gel column chromatography (hexane: ethyl acetate = 9: 1).
Is isolated and produced in the above-mentioned manner to obtain 11 mg (yield 12%) of the title compound. ^The structure was confirmed by ¹ HNMR and IR. Data are the same as described in Example 1.

[0048]

Example 14 Preparation of ethyl 2-oxo-4-phenyl-3-butenoate

110 mg (0.46 mmol) of ethyl 4-methoxy-2-oxo-4-phenylbutanoate was dissolved in 5 ml of ethanol, a small amount of iodine was added, and the mixture was heated under reflux.
Do on time. Add aqueous sodium thiosulfate solution and extract with ether. After drying over anhydrous magnesium sulfate, the solvent was removed, and the title compound 3 was isolated by silica gel column chromatography (hexane: ethyl acetate = 9: 1).
3 mg (36% yield) are obtained. ^The structure was confirmed by ¹ HNMR and IR. Data are the same as described in Example 1.

[0050]

Industrial Applicability According to the present invention, it is possible to provide a method for producing a β, γ-unsaturated α-ketoester by a simple reaction procedure starting from an inexpensive raw material.

Claims (3)

[Claims] Claims: Among γ- alkoxy -α- ketoester (Formula 1 represented by Formula 1, R ¹ is an alkyl group, an aryl group, a vinyl group or a heterocyclic compound,, R ^2, R ³ is a lower alkyl group Is represented by the following formula (2) wherein the alcohol is eliminated by treating the compound with an acid catalyst or a base catalyst (wherein R ¹ is an alkyl group, an aryl group,
It represents a vinyl group or a heterocyclic compound, and R ² represents a lower alkyl group. ) A method for producing a β, γ-unsaturated α-keto ester. [Chemical 2] 2. The method according to claim 1, characterized in that silica gel is used as the acid catalyst. 3. Acetal and 2- (trimethylsiloxy)
Γ-represented by Chemical Formula 1, which is produced from an acrylic ester
The process according to claim 1, characterized in that the alkoxy-α-ketoester is subsequently treated with silica gel without isolation and purification to obtain a β, γ-unsaturated α-ketoester represented by the formula (2). Law.