JPH03161483A - Production of furanone derivative - Google Patents

Abstract

PURPOSE:To obtain the title compound useful as an intermediate for synthesis of pilocarpine hydrochloride, a remedy for glaucoma, industrially and advantageously by treating a dihydrofuranone derivative with an acid catalyst such as a sulfonic acid derivative and then reacting the treated substance with a lower alcohol. CONSTITUTION:A dihydrofuranone derivative shown by formula I (R1 to R3 are H or lower alkyl) is treated with an acid catalyst selected from a sulfonic acid derivative shown by the formula R<4>SO3H [R<4> is H, (halo-substituted) lower alkyl or (substituted) phenyl] and a sulfonic group containing resin and then reacted with an alcohol shown by the formula R<5>OH (R<5> is lower alkyl) to give the objective compound shown by formula II.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention provides compounds of the general formula [IV] (formula Among them, R1 is a hydrogen atom or a lower alkyl group, and RS is a lower alkyl group.

According to the present invention, the desired furanone derivative }IVI
is a dihydrofuranone derivative represented by the general formula [11 (in the formula, Rl. R2 and R3 represent a hydrogen atom or a lower alkyl group)] R'SO,I1 ...... [111
(In the formula, R4 represents hydrogen, a lower alkyl group, a halo-substituted lower alkyl group, a phenyl group, and a substituted phenyl group)
After treatment with an acid catalyst selected from either a sulfonic acid derivative represented by the formula or a resin having a sulfonic acid group, the general formula [1111R501{...
Furanone derivatives represented by the general formula [■1] are produced by reacting with alcohols represented by [1111 (in the formula, R5 represents a lower alkyl group)] It is a compound useful in the preparation of pilocarpine hydrochloride and its derivatives, which are used as medicines, and its production method has been known for a long time. For example, a method of treating a dihydrofuranone derivative represented by general 2[1 with an acetic acid solution of hydrogen bromide is
rahedron, 28, 967 (1972) and Soviet patent USSR. No. 589,243.

However, when the present inventor conducted a study, it was found that the yield was poor under the conditions described and was not practical. In addition, a solution of hydrogen bromide in acetic acid is expensive, and there are other problems such as hydrogen bromide being lost to the outside of the system when heated.

[Problem to be solved by the invention]

The present inventors used a dihydrofuranone derivative [+1 as a starting material, treated it with an acetic acid solution of hydrogen bromide, and then subjected it to an esterification reaction with a lower alcohol [11] to produce a furanone derivative [IV]. Although this method is very simple for laboratory use, it is problematic as an industrial production method because the yield is low and there is a risk that hydrogen bromide will leak out of the reaction system and corrode machinery and equipment. We focused on this fact and investigated various treatment agents other than hydrogen bromide.

As a result, it was discovered that a specific acid catalyst, which is industrially very inexpensive, was the most suitable as a treatment agent for this reaction, and the present invention was completed.

[Means for Solving the Problems] The present invention provides a dihydrofuranone derivative represented by the general formula [1'] (wherein R', R'' and R1 represent a hydrogen atom or a lower alkyl group). Formula [1] R'SO3}1 ......[II]
(In the formula, R4 represents hydrogen, a lower alkyl group, a halo-substituted lower alkyl group, a phenyl group, and a substituted phenyl group)
After treatment with an acid catalyst selected from either a sulfonic acid derivative represented by the formula or a resin having a sulfonic acid group, -m formula [11111? 'oI1...
...[III] (In the formula, RS represents a lower alkyl group) A general 2flVI (wherein R° is hydrogen or a lower alkyl group) R5 represents a lower alkyl group). It concerns j.

In carrying out the present invention, the dihydrofuranone conductor {11} used as the starting material 4 is a known substance, such as Tetrahedronp 28. 967
(1972).

The treatment with a sulfonic acid derivative or a resin having a sulfonic acid group in the present invention can be carried out without a solvent or in a relatively high boiling point solvent such as water, ethylene glycol, methyl cellosolve, dioxane, acetic acid, and xylene.

A series of reactions such as hydrolysis, decarboxylation, isomerization, etc. occur in one step only by treatment with a sulfone MFa conductor or a resin having a sulfonic acid group, and the cihytrofuranone derivative [N is expressed by the general formula [AI (where Rl is the same as above)] ) is converted into an intermediate represented by

The reaction in this acid treatment can be carried out in high yield by distilling off the alcohols produced during the reaction out of the system.

Generally, it is easier to distill off alcohols when they are converted into acetic esters, so it is preferable to coexist acetic acid in the reaction system.

In carrying out the sulfuric acid treatment of the present invention, the amount of the sulfonic acid derivative or the resin having a sulfonic acid group is 0.05 to IO times by weight, preferably 0.1 to 2 times by weight, and the solvent, relative to the dihydrofuranone derivative as the starting material. is used in an amount of 0.2 to 20 times by weight, preferably 0.5 to 5 times by weight. When hydrous acetic acid is used as a solvent, the water content is 1 to 90 wt%, preferably 5 to 30 wt%.

The acid treatment is usually carried out at 60 to 130°C, preferably at 10°C while distilling off ethanol, ethyl acetate, etc. produced by the reaction.
0-120°C for 1-100 hours, preferably lO
Run for ~50 hours.

The intermediate (Al) produced by the acid treatment is separated according to a conventional method and used as a crude product or purified for the next esterification reaction.

The esterification reaction between the intermediate [AI and the alcohol liJ[III] is performed using the raw material alcohol Ju[I[I]
The reaction itself can be used as a solvent, or it can be performed in a solvent such as Hensen, toluene, xylene, etc.

The yield is usually improved by carrying out this reaction in the presence of an acid catalyst or a condensing agent.

Examples of the acid catalyst used in this reaction include inorganic acids such as sulfuric acid, hydrochloric acid, nitric acid, and phosphoric acid, and organic sulfonic acids such as methanesulfonic acid and p-toluenesulfonic acid.

In carrying out this esterification reaction, the intermediate [A
Alcohol [I[11] is 0.5 to 50 times by weight when used also as a solvent, preferably 2 to 10 times by weight, and 1 to 10 times by mole when a solvent such as toluene is used, preferably 1 to 2 times the mole: the solvent is 0.5 to 50 times by weight, preferably 2 to 20 times by weight; the acid catalyst is 0 to 0.2 times by weight,
It is preferable to use each in an amount of 0.001 to 0.05 times by weight.

The reaction is carried out at 50 DEG to 150 DEG C., preferably at the reflux temperature of the solvent, for 0.1 to 50 hours, preferably 0.5 to 10 hours. After the reaction is completed, the desired furanone derivative [TV] is obtained by separation and purification according to a conventional method.

Examples are shown below to explain the embodiments of the present invention in detail.

In addition, the following example shows an example in which a compound of the general formula Ill in which pl, R2, and R3 are all ethyl groups is used as a starting material, but the present invention uses a compound in which Rl, RZ, and R3 are all ethyl groups.
Of course, it also includes the case where 3 is the same or different and is a hydrogen atom or any lower alkyl group.

Example 1 Dihydrofuranone derivative [I] Cl? ', R2 and R3 are both ethyl groups) 536g (1.69m
ol), 180 g of concentrated sulfuric acid, 100 g of water, and 900 g of acetic acid were mixed, and the temperature was raised from 80°C to 115°C over 35 hours. During this time, the low-boiling components that had been collected were distilled off.

After the reaction was completed, the solvent was distilled off under reduced pressure, 500 ml of brine was added, and the mixture was extracted with methylene chloride. (1fx 1 time, 0.2
5f x 2 times).

The organic layer was concentrated under reduced pressure, and ethanol/toluene = 1 was added to the residue.
200 d of the mixture was added and concentrated under reduced pressure to obtain 312 g of a crude product of intermediate [A+].

Ethanol 1.51 for crude oysters! ．． and refluxed for 5.5 hours. After cooling, it was concentrated to obtain 285 g of a residue. This was dissolved in 300 ml of methylene chloride, passed through a column packed with 75 g of silica gel, and eluted with 100 ml of methylene chloride. The eluate was concentrated and then distilled under reduced pressure to obtain furanone derivative [IV] (R' and R4 are ethylene groups)24
9g (yield 74%) at 105-124°C/0.9m
Fraction of mHg. obtained as.

Example 2 Dihydrofuranone derivative (N (R', R2 and R
3 is an ethyl group] 30. Examples l and 1 from Og
15.5 g of the crude raw material prepared in the same manner was dissolved in 120 mN of methanol with 0.5 g of p-}runsulfonic acid, and the mixture was heated under reflux for 4 hours. After cooling, concentrate and add 5 liters of sodium chloride water.
0 ml was added, and 50 ml of acetic acid ester was added three times. The organic layer was washed with 15% brine, sodium anhydrite,
Anhydrous magnesium sulfate was sequentially added to dry the mixture. After filtering the desiccant, it was concentrated and evaporated under reduced pressure to obtain furanone derivatives [IVl (R' is dif)5, R' is j-f-
10.6g (yield: 6l%) at 11-121°C
/0. Obtained as a fraction of 87 mmHg.

Example 3 Dihydrofuranone derivative [1 [R', I? 2 yoko l? 3 are all ethyl groups) 9.50g (30m
mol) to fruit 3. 5. Crude compound synthesized in the same manner as Example 1. Og, n Octal 5.0g (36mmo+
), p-toluene''/:l, 0.2 g of ludonic acid was dissolved in 50 d of toluene and stirred for 2.25 hours. After cooling, 20 ml of saturated sodium chloride water was added to separate the liquid, and the aqueous layer was further separated. Extracted with 20 ml of ethyl acetate.The organic layers were combined and diluted with 3 ml of saturated brine.
It was washed with 0d and dried with anhydrous sodium sulfate. After filtering the desiccant, it was concentrated and purified by silica gel column chromatography (hexane/ethyl acetate - 3/1) to obtain a furanone derivative [IV] (R+ is an ethyl group, RS is an n-Csl
1+9] 5.62 g (66%) was obtained.

Example 4 Benzyl alcohol instead of octanol 3. 82
The reaction was carried out in the same manner as in Example 3 except that 3.69 g (47%) of a furanone derivative was obtained.

Example 5 Trifluoromethanesulfonic acid 200% instead of concentrated sulfuric acid
The reaction was carried out in the same manner as in Example 1, except that g was used, and 230 g (yield: 71%) of a furanone derivative was obtained.

Example 6 The reaction was carried out in the same manner as in Example 1 except that 240 g of p4 luenesulfonic acid was used instead of concentrated sulfuric acid, and 245 g (yield: 74%) of a furanone derivative was obtained.

Example 7 Ion exchange resin (Amberlyst 15) was used instead of concentrated sulfuric acid.
) The reaction was carried out in the same manner as in Example 1, except that 160 g was used, and 125 g (yield: 36%) of a furanone derivative was obtained.

Comparative Example Tetrahedron, 28, 967 (1972
), I performed the following operations. Dihydrofuranone derivative [11 (1?'R2 and R3 are ethyl groups) 2
．． 0 g was dissolved in 10 mfl of 25% hydrogen bromide acetic acid solution and heated under reflux for 50 hours. After cooling and concentration under reduced pressure, water was added and extracted with diethyl ether. The extract was dried with anhydrous sodium sulfate and magnesium sulfate, and the solvent was distilled off.
1.27 g of crude intermediate was obtained.

Next, this intermediate was dissolved in 13 m2 of anhydrous methanol,
P-} Add 0.65 g of luenesulfonic acid anhydrate,
The mixture was heated to reflux for an hour. After cooling and concentrating, water was added and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate water, dried over sodium sulfate, filtered to remove the desiccant, and concentrated to obtain crude product 1.
．． Obtained 0g.

When the obtained crude parabolite was analyzed using '}INMR, the yield of the target product [IV] [R' is ethynolel, R5 is methylene group] was 30%.

〔Effect of the invention〕

As is clear from the Examples and Comparative Examples, furanone derivative rI was prepared using bihydrofuranone derivative [1] as a starting material.
Previously, the only known method for producing V1 was to use hydrogen bromide, which had a low yield and was expensive and highly dangerous as an industrial raw material. A new method for safely producing furanone derivatives [TV] with high yield was provided.

Claims (1)

[Claims] General formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼[I] (In the formula, R^1, R^2 and R^3 represent a hydrogen atom or a lower alkyl group) The dihydrofuranone derivative represented by the general formula [II] R^4SO_3H...[II] (wherein, R^4 is hydrogen, a lower alkyl group, a halo-substituted lower alkyl group, a phenyl group, and After treatment with an acid catalyst selected from either a sulfonic acid derivative represented by (representing a substituted phenyl group) or a resin having a sulfonic acid group, the general formula [III] R^5OH... [III] (In the formula, R^5 represents a lower alkyl group) A general formula characterized by reacting with an alcohol [IV] ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [IV] ( A method for producing a furanone derivative represented by the formula (wherein, R^1 represents hydrogen or a lower alkyl group, and R^5 represents a lower alkyl group).