JPH07108883B2 - 3,3-diacyloxypropionic acid derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to 3,3-diacyloxypropionic acid derivatives which have not been published in the literature.

The compound of the present invention, by alcoholysis,
It can be easily converted to ethyl 3,3-diethoxypropionate or ethyl β-ethoxyacrylate, which is an important synthetic intermediate for the synthesis of heterocyclic compounds such as uracil (see Reference Example below).

[Conventional technology]

Conventionally, as a method for synthesizing ethyl 3,3-diethoxypropionate or ethyl β-ethoxyacrylate,
(1) Method for synthesis from ethyl bromoacetate, triphenylphosphine and ethyl formate using the Wittig reaction [M.
Le.Corre, BuIl.Soc.Chim.Fr., 2005 (1974)], (2)
From ethyl bromoacetate, zinc and triethyl orthoformate
Reformatzsky, a method of synthesis using reactions [NCDen
o, J.Am.Chem.Soc., 69 , 2233 (1947)], (3) A method of reacting acetylene and diethyl carbonate in the presence of a base [W.
J. Croxall et al., J. Am. Chem. Soc., 71 , 1257 (1949)],
(4) Method of adding ethanol to acetylene carboxylic acid or its ethyl ester [F. Strans et al., Ber., 59 , 168]
1 (1926); SH Bertz et al., J. Org. Chem., 47 , 2216 (198
2). ] (5) A method of adding carbon tetrachloride to vinyl acetate or vinyl ethyl ether and then subjecting to alcoholysis [Yukio Takagi, Teruzo Asahara, Journal of Industrial Chemistry, 64 , 1691 (196)
1); Japanese Examined Sho 46-40262; A. Holy, Coll. Czech. Chem. Commu
n., 39 , 3177 (1974), but the method (1) requires a large amount of expensive triphenylphosphine and the yield is poor, and the method (2) must be performed under anhydrous conditions. Yield is poor.The method (3) is poor in yield because of reaction under pressure of acetylene.The method (4) requires expensive acetylene carboxylic acids and is difficult to implement in a factory.
In the method (5), a large amount of HC1 is produced as a by-product during the alcoholysis step, which causes a problem of corrosion of the reaction vessel, and the total yield is not good.

Due to these drawbacks, there has been no method for producing ethyl 3,3-diethoxypropionate or ethyl β-ethoxyacrylate which can be industrially carried out.

[Problems to be solved by the invention]

The present inventors have overcome the drawbacks of the prior art, and simply and inexpensively 3,
The present invention has been completed by finding a 3,3-diacyloxypropionic acid derivative capable of producing ethyl 3-diethoxypropionate or ethyl β-ethoxyacrylate.

[Means for solving problems]

General formula of the invention (In the formula, R ¹ is a lower alkyl group, R ² is a hydrogen atom or R ¹ CO group.) A novel 3,3-diacyloxypropionic acid derivative represented by the general formula R ¹ COOH- (II) (wherein R ¹ is a lower alkyl group) and the general formula CH ₂ = CH-X- (III) (wherein X is a halogen atom or an acyloxy group) It can be produced by reacting an olefin represented by the formula (1) with carbon monoxide and an oxidizing agent.

Examples of palladium catalysts that can be used include palladium metal such as fine palladium powder and palladium black, palladium salts such as halides, acetates and nitrates, and palladium supported on carriers such as carbon and alumina. it can. The amount of the catalyst used can be appropriately selected within the range of 1/1000 to 1/5 equivalent to the olefin.

Examples of suitable carboxylic acids include formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, pivalic acid, lauric acid, myristic acid, palmitic acid, stearic acid, trifluoroacetic acid and the like. However, acetic acid is preferable from the economical point of view. It is necessary that the amount of the carboxylic acid used is stoichiometric or more with respect to the olefin, and the excess amount can also serve as the diluent.

The olefin represented by the general formula (III), which is the raw material of the present invention, is industrially available, and examples thereof include vinyl acetate, vinyl propionate, vinyl fluoride, vinyl chloride, vinyl bromide and the like. Vinyl acetate is preferred in terms of economy, reaction efficiency. The partial pressure of carbon monoxide may be the self-pressure at the reaction temperature used, or it may be diluted with an inert gas that does not participate in the reaction. It is also possible to carry out under elevated pressure, and in this case, from the viewpoint of stability, a range of up to 60 atmospheric pressure is preferred, but higher pressure can be used if desired.

As the oxidizer which can be used, peroxides such as oxygen, hydrogen peroxide, peracetic acid, t-butyl peroxide, di-t-butyl peroxide, cupric chloride, cupric bromide, ferric chloride, sodium nitrate. Examples thereof include inorganic oxidizing agents such as lithium nitrate, potassium nitrate, and manganese dioxide, and organic oxidizing agents such as quinone. These may be used together, but it is preferable to use oxygen from the viewpoint of economy. The amount of the oxidizing agent used is a theoretical amount or an excess amount with respect to the olefin.

In the reaction, addition of carboxylic acid anhydride resulted in 3,3-
A mixed acid anhydride of diacyloxypropionic acid tends to be obtained, and may be added if desired. The carboxylic acid anhydride used is preferably the same acid anhydride as the carboxylic acid represented by the general formula (II), especially acetic anhydride, considering the post-treatment. If desired, an excess amount can be used as a diluent.

From the viewpoint of reaction efficiency, it is preferable to add a copper catalyst and / or an alkali metal salt. As the copper catalyst, metallic copper, cuprous salt or cupric salt can be used. Examples of suitable copper salts include copper acetate, copper acetylacetonate, copper chloride,
Copper bromide, copper iodide, copper nitrate and the like are included. The amount of copper catalyst used can range from 1/500 to 2 molar equivalents relative to the olefin. Suitable alkali metal salts include, for example, sodium chloride, lithium chloride, potassium chloride, cesium fluoride, potassium fluoride, sodium bromide, potassium bromide, sodium iodide, potassium iodide, sodium acetate, potassium acetate and the like. Can be used. When a palladium salt is used as the palladium catalyst, it can be first reacted with an alkali metal halide and used as a palladium ate complex. The amount of the alkali metal salt used can be selected within the range of 2 equivalents relative to the olefin.

Furthermore, if desired, it is possible to use additional solvents which do not participate in the reaction. The individual solvents used can form a single phase. Alternatively, a solvent that can form the second liquid phase may be used. Examples of these include, for example, ether solvents such as diethyl ether, tetrahydrofuran and dioxane, hydrocarbon solvents such as hexane, cyclohexane, benzene, toluene and xylene, halogenated hydrocarbon solvents such as dichloromethane, chloroform and chlorobenzene. Can be mentioned.

The reaction temperature can be carried out at ambient temperature, but elevated temperatures can also be used, for example in the range 20 to 150 ° C. or higher.

Hereinafter, it will be described in more detail with reference to Examples and Reference Examples.

Example 1 Add palladium acetate (22.4 mg, 0.1 mmo
l), cupric chloride (26.9 mg, 0.2 mmol) and sodium chloride (58.4 mg, 1 mmol) were charged and the system was replaced with oxygen. A balloon of carbon monoxide and oxygen mixed gas was attached, acetic acid (5 ml), acetic anhydride (3 ml) and vinyl acetate (0.396 ml, 4 mmol) were added, and the mixture was stirred at 80 ° C. for 20 hr. The solvent was evaporated from the reaction mixture, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ether. After washing with water, it was dried over anhydrous sodium sulfate. By distilling off the solvent, 3,3-diacetyloxypropionic acid acetic acid mixed acid anhydride was obtained in a yield of 41%.

3,3-Diacetyloxypropionic acid acetic acid mixed acid anhydride ¹ H-NMR (CDCl ₃ ): δ 2.10 (6H, s), 2.23 (3H, s), 2.96
(2H, d, J = 5.6Hz), 6.98 (1H, t, J = 5.6Hz). IR (naet): νc = o 1830,1760 cm ^-1 . Example 2 Put a glass tube in a 30 ml autoclave made of stainless steel, and palladium acetate (22.4 mg, 0.1 mmol), cupric chloride (26.9 m
g, 0.2 mmol) and sodium chloride (58.4 mg, 1 mmol) were added. Further, acetic acid (5 ml), acetic anhydride (3 ml) and vinyl acetate (0.369 ml, 4 mmol) were added and the autoclave was sealed. After replacing the inside of the system with oxygen, carbon monoxide and oxygen were applied at 10 atm, respectively, and the mixture was stirred at 80 ° C. for 20 hours. The solvent was evaporated from the reaction mixture, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ether. After washing with water, it was dried over anhydrous sodium sulfate. By distilling off the solvent, a mixture of 3,3-diacetyloxypropionic acid acetic acid mixed anhydride and 3,3-diacetyloxypropionic acid (4.3: 1) was obtained in a yield of 770.2 mg (86
%).

3,3-Diacetyloxypropionic acid ¹ H-NMR (CDCl ₃ ): δ2.08 (6H, s), 2.87 (2H, d, J = 5.8H
z), 6.98 (1H, t, J = 5.8Hz), 8.8 (1H, br). IR (naet): νc = o 1750,1720 cm ^-1 .ν _OH 3200 cm ^-1 .Example 3 Repeating Example 2 with the amount of sodium chloride being 29.2 mg (0.5 mmol), 3,3-diacetyloxypropionic acid acetic acid mixture A mixture of acid anhydride and 3,3-diacetyloxypropione (6.7: 1) was obtained in a yield of 768.8 mg (85%).

Example 4 Instead of palladium acetate, palladium chloride (8.9 mg, 0.1 m
mol), the amount of sodium chloride is 29.2 mg (0.5 mmol)
Example 2 is repeated as above to obtain 3,6 diacetyloxypropionic acid acetic acid mixed acid anhydride in a yield of 686.2 mg (74%).

Example 5 Example 2 was repeated without adding sodium chloride to give 3,3
-Diacetyloxypropionic acid acetic acid mixed acid anhydride was obtained in a yield of 516.7 mg (56%).

Example 6 Cupric chloride was not added, and the amount of sodium chloride was adjusted to 29.2.
Repeating Example 2 as mg (0.5 mmol) yielding 3,3-diacetyloxypropionic acid acetic acid mixed anhydride 435.
Obtained at 7 mg (47%).

Example 7 Example 1 was repeated without acetic anhydride to give 3,3-diacetyloxypropionic acid in a yield of 215.8 mg (28%).

Example 8 Example 1 was repeated using 0.378 ml (4 mmol) of acetic anhydride to give a mixture of 3,3-diacetyloxypropionic acid acetic acid mixed anhydride and 3,3-diacetyloxypropionic acid (1: 1.3). Yield 317.3 mg (38%).

Example 9 Example 2 in which carbon monoxide and oxygen were applied at 20 atm.
By repeating the above procedure, 3,3-diacetyloxypropionic acid acetic acid mixed acid anhydride was obtained in a yield of 829.4 mg (89%).

Example 10 Instead of sodium chloride, lithium chloride (21.4 mg, 0.5 mm
Example 2 was repeated using 63) mg of a mixture of 3,3-diacetyloxypropionic acid acetic acid mixed anhydride and 3,3-diacetyloxypropionic acid (1: 1.3).
%).

Example 11 Palladium acetate (11.4 mg, 0.05 mmo
l), cupric chloride (538.0 mg, 4 mmol), and sodium chloride (29.2 mg, 0.5 mmol) were added to replace carbon monoxide in the system. A carbon monoxide balloon was attached, acetic acid (2.5 ml), acetic anhydride (1.5 ml) and vinyl acetate (0.185 ml, 2 mmol) were added, and the mixture was stirred at 80 ° C. for 20 hr. The same post-treatment as in Example 1 was carried out to obtain a mixture of 3,3-diacetyloxypropionic acid acetic acid mixed anhydride and 3,3-diacetyloxypropionic acid (3.3: 1) in a yield of 143.5 mg (32%). Was given.

Example 12 Manganese dioxide (174 mg, 2 mmol) instead of cupric chloride
Example 11 was repeated using and p-benzoquinone (5.4 mg, 0.05 mmol). A mixture of 3,3-diacetyloxypropionic acid acetic acid mixed anhydride and 3,3-diacetyloxypropionic acid (1.8: 1) was obtained in a yield of 165 mg (38%).

Example 13 Put a glass tube into a 20 ml autoclave and put in palladium acetate (22.4 mg, 0.1 mmol), cupric chloride (67.2 mg, 0.5 mmol),
Sodium chloride (146 mg, 2.5 mmol), acetic acid (5 ml) and acetic anhydride (2 ml) were added. After sealing the autoclave,
After degassing, vinyl fluoride (224 ml, about 10 mmol) was introduced, and further oxygen (10 atm, about 9 mmol) and carbon monoxide (10 atm, about 9 mmol) were injected under pressure. After heating and stirring at 80 ° C. for 14 hours, the solvent was distilled off from the contents under reduced pressure, an aqueous ammonium chloride solution was added, and the mixture was extracted with ether. After the extract was dried over anhydrous sodium sulfate, the ether was distilled off to give 3,3
-Diacetyloxypropionic acid acetic acid mixed acid anhydride was obtained in a yield of 372 mg (1600% per Pd).

Example 14 Put the glass tube in a 30 ml autoclave made of stainless steel,
Palladium acetate (22.4mg, 0.1mmol), cupric chloride (26.9mg)
mg, 0.2 mmol), sodium chloride (58.4 mg, 1 mmol), sodium acetate (328.1 mg, 4 mmol), acetic acid (5 ml) and acetic anhydride (3 ml) were put and the autoclave was sealed. After degassing the autoclave, vinyl chloride (240 ml, about 10 mmol) was introduced, and carbon monoxide and oxygen were applied at 10 atm to 80 ° C.
And stirred for 20 hours. The solvent was distilled off from the reaction mixture, saturated ammonium chloride was added, and the mixture was extracted with ether. After washing with water, it was dried over anhydrous sodium sulfate. The solvent was distilled off to give 3,3-
Diacetyloxypropionic acid acetic acid mixed anhydride and 3,3
A mixture of diacetyloxypropionic acid (3: 1) was obtained with a yield of 174.0 mg. During extraction, the aqueous layer was adjusted to pH 1 with 2 ml of 1N hydrochloric acid and extracted with ether. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 3,3-diacexypropionic acid in a yield of 15.0 mg. Total yield 0.86 mmol (pd
860%).

Example 15 Add palladium acetate (22.4 mg, 0.1 mmo
l), cupric chloride (26.9 mg, 0.2 mmol) and sodium chloride (58.4 mg, 1 mmol) were charged and the system was replaced with oxygen. A balloon containing carbon monoxide and oxygen mixed gas was attached, and propionic acid (5 ml), propionic anhydride (3 ml) and vinyl acetate (36
(9 μl, 4 mmol) was added, and the mixture was stirred at 80 ° C. for 20 hours. The solvent was distilled off from the reaction mixture, saturated aqueous ammonium chloride solution was added, the mixture was extracted with ether, and dried over anhydrous sodium sulfate. Concentration yielded a mixture of 3,3-dipropionyloxypropionic acid propionic acid mixed anhydride and 3,3-dipropionyloxypropionic acid (2.3: 1) yielding 622.6 mg (60%).
%).

3,3-Dipropionyloxypropionic acid Propionic acid mixed acid anhydride ¹ H-NMR (CDCl ₃ ): δ1.13 (6H, t, J = 7.8Hz), 1.18 (3H,
t, J = 6.4Hz), 2.35 (4H, q, J = 7.8Hz), 2.35 (2H, q, J =
6.4Hz), 2.96 (2H, d, J = 5.4Hz), 7.00 (1H, t, J = 5.4H)
z). IR (neat): νc = o 1830,1768cm ^-1 .3,3-dipropionyloxypropionic acid ¹ H-NMR (CDCl ₃ ): δ1.14 (6H, t, J = 7.8Hz), 2.37 (4H,
q, J = 7.8Hz), 2.84 (2H, d, J = 6.0Hz), 6.99 (1H, t, J =
6.0Hz), 9.67 (1H, br). IR (neat): ν _ON 3550cm ^-1 .νc = o 1770cm ^-1 .Example 16 Add palladium acetate (22.4 mg, 0.1 mmo
l), cupric chloride (26.9 mg, 0.2 mmol) and sodium chloride (58.4 mg, 1 mmol) were charged and the system was replaced with oxygen. Attach a balloon of carbon monoxide and oxygen mixed gas and add acetic acid (5 ml),
Acetic anhydride (3 ml) and vinyl propionate (0.436 ml, 4
mmol) was added and the mixture was stirred at 80 ° C. for 20 hours. The solvent was evaporated from the reaction mixture, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ether. The extract was dried over anhydrous sodium sulfate and then concentrated to obtain 347.6 mg of an acid anhydride containing 3,3-diacetyloxypropionic acid acetic acid mixed acid anhydride as a main component. From ¹ H-NMR of this product, the integral ratio of the peak derived from the propionyl group and the peak derived from the acetyl group was 1: 3.7.

Reference example 1 In a 25 ml side-arm flask, p-toluenesulfonic acid (8.4 mg,
0.04mmol), ethanol (5ml), benzene (5ml), 3,
3-diacetyloxypropionic acid acetic acid mixed acid anhydride (7
(70 mg, 3.3 mmol) was added and n- was used as the GLC internal standard.
Nonane (151.6 mg, 1.182 mmol) was added and the mixture was heated under reflux for 42 hours. As a result of gas chromatography quantifying the reaction mixture, a mixture (1: 3.7) of ethyl 3-ethoxyacrylate and ethyl 3,3-diethoxypropionate was obtained in a yield of 70%.

Ethyl 3-ethoxyacrylate ¹ H-NMR (CDCl ₃ ): δ1.27 (3H, t, J = 7.5Hz), 1.35 (3H,
t, J = 7.5Hz), 3.88 (2H, q, J = 7.5Hz), 4.13 (3H, q, J =
7.5Hz), 5.17 (1H, d, J = 12.6Hz), 7.55 (1H, d, J = 12.6H)
z). .. IR (neat) νc = o 1710cm -1 νc = o 1624cm -1 3,3- di-ethoxy ethyl propionate _{^{1 H-NMR (CDCl 3)}} : δ1.21 (6H, t, J = 7.4Hz), 1.25 (3H,
t, J = 7.0Hz), 2.63 (2H, q, J = 6.0Hz), 3.60 (2H, ddq, J
= 13.1, 9.3 and 7.4Hz), 4.12 (2H, q, J = 7.0Hz), 4.93 (1
H, t, J = 6.0Hz). IR (neat): νc = o 1740cm ^-1

Claims (1)

[Claims] 1. A general formula (In the formula, R ¹ is a lower alkyl group, R ² is a hydrogen atom or R ¹ CO group.) A 3,3-diacyloxypropionic acid derivative.