JPS6368582A - Production of alpha,alpha-dimethyl-delta-valerolactone - Google Patents

Abstract

PURPOSE:To easily obtain the titled compound useful as a remedy for arteriosclerosis and hyperlipoproteinemia in high yield, by adding dimethylpentenoic acid to a solution of hydrogen bromide and cyclizing the resultant dimethylbromovaleric acid by alkali treatment. CONSTITUTION:2,2-Dimethyl-5-bromovaleric acid is produced by adding 2,2- dimethyl-4-pentenoic acid to solution prepared by dissolving hydrogen bromide in a solvent and subjecting the acid to addition reaction of hydrogen bromide. The objective compound can be produced by treating and cyclizing the synthesized acid with an alkali. The 2,2-dimethyl-4-pentenoic acid used as a raw material is preferably synthesized by heating allyl isobutyrate in the presence of sodium hydride or lithium hydride.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to a method for producing α,α-dimethyl-δ-valerolactone. More specifically, anti-arteriosclerosis tablets, anti-lipidic protein-excess tablets, such as Lopid (manufactured by Parke Davis, USA) CH.

This invention relates to a method for producing α,α-dimethyl-δ-valerolactone, which is useful as a CH3 raw material for compounds having a C)hcHzcHz CCOOH group, such as CHl.

Prior Art Conventionally, α,α-dimethyl-6-valerolactone (hereinafter referred to as D
The following methods are known as methods for producing VL (abbreviated as VL).

(Method for reducing the anhydride of 112,2-dimethylglucuric acid.

The anhydride of 2,2-dimethylglutaric acid, which is the raw material for this method, is synthesized using isobutyraldehyde and acrylonitrile as starting materials through a number of steps including Michael addition reaction, hydrolysis reaction, oxidation reaction, and lactonization reaction. The yield is also low.

Moreover, the reduction of nucleic acid anhydrides requires the use of complex and difficult-to-obtain ruthenium-based catalysts, and has the drawback of low yields. (B
ul, Chem, Soc, Jpn+ 57゜(
2) A method of alkylating δ-valerolactone using methyl iodide and diisopropyllithiumamide.

This method has the disadvantage that both δ-valerolactone and diisopropyllithium amide are expensive, and the product obtained is also expensive. (J, C, S.

Chem, Comm, (1973), 711
)(3) 4-methyl-1,4-bentanediol to 9
7-100% sulfuric acid and 100% formic acid, or 97-100
% sulfuric acid and copper oxide and -carbon oxide, then l
(How to react with 0.

The raw material 4-methyl-1,4-bentanediol in this method is produced by reacting T-butyrolactone and methyl bromide in the presence of magnesium, but since this reaction has a low reaction yield, the resulting α, α- dimethyl-δ
-The yield of valerolactone is also a drawback.

(Chem, Lett, (1982), 118
7) A method of oxidizing (412,2-dimethyl-1,5-bentanediol) using allyl halide and a palladium catalyst.

2,2-dimethyl-1,5-bentanediol, which is a raw material in this method, is synthesized by reducing diester or acid anhydride of 2,2-dimethylglucuric acid. Therefore, as shown in conventional method (1), synthesis of the diester or acid anhydride is not easy, and its reduction is also difficult.
etc., making the process complicated and expensive. Furthermore, lactonization produces the following lactone by-products,
There is a drawback that the selectivity of DVL is low.

(J, org, Chem, 48. 128
6 (1983) )+512.2-dimethyl 1.5
- A method of dehydrogenating and lactonizing bentanediol using a ruthenium-based catalyst.

Obtaining the raw material 2,2-dimethyl=1,5-bentanediol in this method is not easy as shown in the conventional method (4). Furthermore, lactonization produces the above-mentioned isomeric lactones, which has the drawback of low selectivity for DVL.

(Tetrahedron, Lett, 24.26
77 (1983)) (Method of reacting 612,2-dimethylvinylbutyric acid ester and cobalt carbonyl.

This method uses a highly toxic reagent such as cobalt carbonyl, and the reaction is carried out at a high temperature and pressure of 240° C. and 290 atmospheres, so it requires a high-temperature, high-pressure apparatus and is difficult to operate.

(Helgie Patent No. 616141) As mentioned above, in conventional methods, raw materials and reaction reagents are difficult to obtain or synthesize, resulting in high costs, low reaction yields, or DVL selectivity. is not good, and a large amount of isomers are produced. Therefore, a method for synthesizing DVL suitable for industrialization has not yet been established.

OBJECT OF THE INVENTION The present invention has been made to overcome the drawbacks of conventional methods, and its purpose is to easily and with high yield using easily available raw materials without using special or expensive chemicals. The object of the present invention is to provide a method for manufacturing DVL economically.

Composition of the Invention In order to achieve the above object, the present inventors conducted extensive research and found that 2,2-dimethyl which can be easily obtained by heating isobutyric acid allyl ester in the presence of sodium hydride or lithium hydride. Using -4-pentenoic acid as a raw material, hydrogen bromide is added to a solution containing hydrogen bromide to synthesize 2,2-dimethyl-5-bromovaleric acid, which is then treated with an alkali. It has been found that DVL can be easily produced and obtained in high yield. Based on this knowledge, we have completed the present invention.

The synthesis process is shown as follows.

2,2-dimethyl-4-pentenoic acid (hereinafter abbreviated as DMP), which is a raw material in the present invention, can be easily obtained by transferring the allyl group of isobutyric acid allyl ester.

In this method, 1.0 to 1.6 times the mole of sodium hydride or lithium hydrogen is charged to the solvent and allyl isobutyrate in a reaction vessel, and the temperature is 80 to 130°C, preferably 11
Heat and stir at 0 to 120°C. Subsequently, allyl isobutyrate is added dropwise to this container over a period of 1 to 8 hours, and then the mixture is aged with stirring at 80 to 130° C. for 1 to 5 hours, and after cooling, methanol and water are added to stop the reaction. Separate this liquid into a solvent layer and an aqueous layer, and make the aqueous layer acidic (pH = 1) with hydrochloric acid.D
MP is released. This is extracted with an organic solvent and separated by accumulation or the like.

Examples of solvents used in this rearrangement step include benzene,
Examples include toluene and dioxane.

Examples of solvents used for extracting DMP include benzene, toluene, hexane, ethyl acetate, chloroform,
Examples include ethyl ether.

The addition reaction of hydrogen bromide to DMP is 0.5 to DMP.
Add DMP to a solvent that has absorbed ~1.5 times the mole of hydrogen bromide.
Add the solution dissolved in a small amount of solvent and heat to -30 to 50℃.
This is done by aging for 0.5 to 5 hours. Examples of solvents used for this include hexane, pentane, ether, toluene, and carbon tetrachloride.

Examples include benzene, dioxane, T)IF, acetic acid, and the like.

The amount of the solvent used to dissolve hydrogen bromide is 1 to 25 times, preferably 8 to 20 times, the weight of DMP. Further, in order to add DMP to the hydrogen bromide solution, it is preferable to use the same solvent in which the DMP is dissolved as the solvent in which the hydrogen bromide is dissolved, from the viewpoint of solvent recovery. The amount of solvent used is D
It is 1 to 5 times the weight of MP, preferably 1 to 3 times.

This addition of hydrogen bromide to DMP requires that the bromide be added to the terminal position (position 5) of DMPO. Addition at the 4-position is preferable because a five-membered ring lactone is produced as a by-product during alkali treatment.

The conventional method of adding hydrogen bromide to an olefin, in which hydrogen bromide is blown into an olefin, produces a five-membered ring lactone as a by-product.

However, the above-mentioned method of adding DMP to a solution of hydrogen bromide in a solvent does not produce a five-membered ring lactone as a by-product, so this method is necessary.

According to this method, hydrogen bromide can be easily added without using a radical initiator such as peroxide as a catalyst. Therefore, after the reaction is complete, there is no need to remove the catalyst or the compounds produced by the decomposition of the catalyst, making it easy to purify, and there is no need to be careful when handling the peroxide catalyst, making operation easy. have

When 2,2-dimethyl-5-bromovaleric acid (hereinafter referred to as DMBr) obtained by addition of hydrogen bromide is treated with an alkali, the ring is closed and DVL is obtained.

Alkaline treatment is performed using 5-50% alkaline water containing 1.0-3.0 times the mole of alkali relative to DMBr = ? b,
The mixture is mixed and stirred at 0 to 50°C for 30 minutes to 3 hours. After the reaction, hydrochloric acid is added to the reaction solution to adjust the pH to 1, and the mixture is separated into DVL and aqueous layers to obtain DVL.

The alkali for the alkali treatment includes alkali metal hydroxides and carbonates such as Na0Il and KOH.

Examples include NazC= , K, CO, and the like. The amount is 1.0 mol of alkali relative to DMBr, and 1.
Q to 3.0 times the mole, preferably 1.1 to 2.0 times the mole.

The DVL thus obtained has high purity, but if even higher purity is required, it may be purified by distillation.

Example 1 100 ml of hexane was charged into a 40 flask equipped with a stirrer, a thermometer, and a condenser, and the flask was cooled to -25°C.

6.70 g of hydrogen bromide gas was blown into this while being shielded from light and absorbed. A solution of DMPIOg dissolved in 15 ml of hexane was added to this solution at -25° C. under light shielding, and the mixture was aged and stirred for 3 hours while gradually raising the temperature to room temperature.

Thereafter, the reaction solution was concentrated under reduced pressure, and the obtained oily concentrate 17
．． 80 ml of 10% Na2CO3 water was added to 31 g, and the mixture was stirred at room temperature for 3 hours to perform a ring-closing reaction. After adding 10 ml of concentrated hydrochloric acid to the obtained liquid to adjust the pH to 1, the mixture was extracted with chloroform, dried, and concentrated under reduced pressure.

With this, DVL! 190g (yield 99.0%,
'f! , 97.7%). This is purified by distillation to achieve high purity (99.5%, boiling point 108-113℃).
/20 maHg) was obtained.

Example 2 In a four-loaf flask equipped with a stirrer, thermometer, and condenser, 6
40.6g of 0% sodium hydride and 50ml of toluene
The mixture was heated and stirred at 110°C. To this, 100 g of allyl isobutyric acid was added dropwise over 5 hours, and after the dropwise addition, the mixture was further heated and stirred at 110° C. for 3 hours.

After the reaction was completed, the mixture was cooled to room temperature, and 18 ml of methanol was added to decompose unreacted sodium hydride.

Then, 200 ml of water was added to dissolve insoluble matter, and then the mixture was decomposed into a toluene layer and an aqueous layer.

The separated aqueous layer was made acidic (pH 1) with concentrated hydrochloric acid, and the resulting oil layer was collected. The aqueous layer was extracted with toluene, the extracted toluene solution was combined with the previously collected oil layer, concentrated, and then distilled under reduced pressure to obtain 1 piece of DMP.

First stop ~65°c/2mmtlg 2.7g Main stop 65~73'c/2mmtlg 85.
The yield of 5g was 85.5% (purity 97.9%).

85.5 g of this DMP was dissolved in 145 ml of hexane, and at room temperature, 1 ml of hexane containing 58.5 g of 1 lBr was dissolved.
The mixture was added to 500 ml of solution and left to age with stirring at room temperature for 2 hours.

This was mixed with 10% NazCOt 680 in the same manner as in Example 1.
A ring-closing reaction was performed by treatment with rnl. The obtained DVL was 82.9g (82.9% yield from allyl isobutyrate).
) (purity 96.5%).

Example 3゜Pour 100 ml of hexane into the reaction vessel of Example 1,
3.55 g of 1 lBr was blown and absorbed at 0°C. A solution prepared by dissolving 5.0 Og of DMP in 10 ml of hexane was added dropwise to this solution at 0° C. over 15 minutes, and then the mixture was stirred and aged for 3 hours while gradually raising the temperature to room temperature.

Thereafter, in the same manner as in Example 1, 50% of 10% Na2COi water was used.
4.97 g of DVL (yield 99.3%)
, purity 99.2%) was obtained.

Example 4゜Pour 100 ml of hexane into the reaction vessel of Example 1,
4.5 g of tlBr was injected and absorbed at -20°C. Add DMP to this solution7. A solution of OOg in 10ml hexane was added all at once at -20°C. Thereafter, the mixture was stirred and aged for 3 hours while gradually raising the temperature to room temperature.

Thereafter, 65 ml of 10% NazCOz water was added as in Example 1.
6.73 g of DVL (yield 96.1%, purity 97.3%) was obtained.

Example 5 To 100 ml of hexane containing 4.40 g of HBr,
0℃.

Under light shielding, HBr was blown at 0.15 g/min, and DMPlog was dissolved in 15 ml of hexane.
It was added over about 60 minutes at a dropwise rate of 5 ml/min. At the same time as the dropwise addition was completed, the blowing of HBr was stopped, and the mixture was stirred for 45 minutes while gradually raising the temperature from 0°C to 15°C.

Then, as in Example 1, 80 m of 10% NazCO3 water was added.
1, 9.75 g of DVL (yield 97.5%,
A purity of 97.2%) was obtained.

Comparative Example 1゜Into the reaction vessel of Example 1, DMPlog, hexane 100
ml, add 100 mg of benzoyl peroxide to this, and add 0.15 g/m of HBr gas at room temperature while stirring.
I blew it in for 1 hour. After the blowing was completed, the mixture was stirred and aged for 2 hours. Then, as in Example 1, 10% Na and CO were added.

It was treated with 10 ml of water to close the ring.

The yield of DVL was 85.3% and the five-membered ring lactone was 8.5%.

3.4% of unknown substances were produced.

Effects of the Invention The method of the present invention has the following advantages.

1) DMP, which is easily obtained from isobutyric acid allyl ester, is used as a raw material, and DVL can be obtained in a higher yield than this, so it can be obtained easily and inexpensively.

2) Since it can be produced without using a catalyst and without producing by-products such as five-membered ring lactones, there is no need to separate by-products, catalysts, and their decomposition products, making it easy to purify and save time. It is easy to manufacture.

Claims (1)

[Claims] 1) 2,2-dimethyl-
α,α-dimethyl-, which is characterized in that 2,2-dimethyl-5-bromovaleric acid is synthesized by an addition reaction of hydrogen bromide by adding 4-pentenoic acid, and this is treated with an alkali to undergo ring closure. Method for producing δ-valerolactone. 2) 2,2-dimethyl-4-pentenoic acid is synthesized by heat-treating allyl ester of isobutyric acid in the presence of sodium hydride or lithium hydride, according to claim 1. A method for producing α,α-dimethyl-δ-valerolactone.