JPS6377837A - Production of cyclopentenone derivative - Google Patents

Abstract

PURPOSE:To easily obtain a cyclopentenone derivative useful e.g. as an intermediate for pharmaceuticals such as prostaglandin, etc., in high yield on an industrial scale, by carrying out the rearrangement of a furan carbinol derivative in a solvent composed mainly of water at a pH within a specific range. CONSTITUTION:The objective 3-hydroxy-4-cyclopentenone derivative of formula II and 4-hydroxy-2-cyclopentenone derivative of formula III can be produced by the rearrangement reaction of a furan carbinol derivative of formula I (R is H or 1-6C alkyl; n is 4-8) [e.g. alpha-(omega-methoxycarbonylhexyl)furfuryl alcohol] in a solvent composed mainly of water (e.g. water or mixture of water and ethylene glycol, methanol, acetic acid, tetrahydrofuran, etc.) at 3.5-6pH, especially 3.5-5pH.

Description

[Detailed Description of the Invention] <Industrial Application Field> The present invention provides general formulas (1) and (11) (I)
ε■] (wherein, IL represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and n represents an integer of 4 to 8).
Hydroxy-4-cyclobentenone derivative (I) and 4-
The present invention relates to a method for producing cyclopentene 223i isomer, which is a mixture of hydroxy-2-cyclobentenone and [(1L).

<Prior art> The cyclobentenone derivatives represented by the above general formulas (1) and (II) are useful as a mixture thereof, or as individual compounds after dividing them, as intermediates for pharmaceutical f4 drugs, etc. and especially 3-hydroxy-4
- Cyclobentenone derivative (I) is extremely important as a trI form among pharmaceuticals such as prostaglandins.

Conventionally, the following method is known as a method for producing such a cyclobentenone derivative from a furancarbinol derivative.

1) A method of adding a small amount of polyphosphoric acid to a water:acetone (l:2 volume ratio) mixed solvent, heating and stirring (Tetrahe
drone Lett,, 181181-1184I)
A method of reacting with an acidic solvent in a mixed solvent of dioxane and water (8:2 volume ratio) (Japanese Unexamined Patent Publication No. 127462/1983) <Problems to be solved by the invention> However, none of the above known methods Because it uses a mixed solvent with water that is mainly a water-soluble organic solvent, there are problems such as complicated isolation of the product after the reaction and a low yield of the target product. Therefore, the answer was that it was not an industrially advantageous method.

For these reasons, the present inventors have improved the above-mentioned drawbacks and have produced the general formula C with industrial ease and high yield.
As a result of studies aimed at producing cyclobentenone derivatives represented by I) and (]■), the present invention was arrived at.

Means for Solving Problems〉 The non-invention is to use a furancarbinol derivative represented by the general formula (III) (wherein R and n have the same meanings as above) in a solvent containing water as the main solvent. Among them, 3-hydroxy-4-cyclobentenone derivatives and 4-hydroxy-2-cyclobentenone derivatives represented by the general formulas (I) and (If), which are characterized by rearrangement at pH 8.5 to 6. The present invention proposes a method for producing a cyclopentynone derivative containing a mixture of the following.

One used as a raw material in non-invention! Burial Ceremony (II
The furan carbinol derivative represented by I) can be synthesized using, for example, 1) a method in which furan is used as a raw material and synthesized by Friedel-Crafts reaction and reduction reaction (Japanese Patent Application Laid-open No. 127462/1982); If) furan and aldehydes are synthesized by a basic How to react in the presence of study medium CTatrt & hedroriLet
t,, Ia 18.1131-1184 (197
7) It can be produced by one method such as [6■].

The solvent used in the rearrangement reaction of the present invention has water as its main solvent, and may be water alone or a mixed solvent mainly composed of water mixed with a small amount of other solvents. Here, other organic solvents include, for example, ethylene glycol, 1,8-propanediol, methanol, ethanol, dioxane, tetrahydrofuran, DMF, DM.
80゜ethyl acetate, acetic acid, dichloromethane, toluene,
aliphatic or aromatic hydrocarbons such as dimethyl ether,
Examples include solvents that are inert to the reaction of alcohols, fatty acids, ethers, esters, halogenated hydrocarbons, and the like. However, in general, there is no particular advantage in coexisting water and these universal solvents.

The amount of solvent to be used is usually 10 to 100 times, preferably 80 to 80 times, the amount of the raw material furancarbinol derivative, excluding the amount of water used.

Although this reaction does not necessarily require a catalyst, its use is effective because the addition of a catalyst improves the reaction rate and increases the reaction rate.

When a catalyst is used in this reaction, examples of the catalyst include octametal salts, organic quaternary ammonium salts, surfactants,
Examples include alcohol.

For example, sodium, potassium, magnesium, zinc, iron, calcium, manganese,
Examples of organic quaternary ammonium salts include phosphates, sulfates, chlorides, bromides, oxides, organic fatty acid salts, and organic sulfonates of cobalt, aluminum, etc.
Examples of surfactants include tetrabutylammonium bromide, benzyltrimethylammonium chloride, tricaprylmethylammonium chloride, dodecyltrimethylammonium chloride, caprylbenzyldimethylammonium chloride, and examples of surfactants include higher fatty acid salts, polyoxyethylene alkylphenol ether, and Examples of the alcohol include methanol, ethanol, ethylene glycol, etc., which were exemplified as solvents above, and may be used alone or as a mixture.

When using a catalyst, its use ■ is usually for p-based furancarbinol visits! /200~5x1! However, outside this range is also applicable.

The catalyst used here can be recovered and reused after the reaction is completed.

The pH of the reaction system is preferably in the range of 8.5-6, more preferably in the range of 8.5-5.

Acids used to maintain such pEI include:
Examples include common inorganic salts such as hydrochloric acid, sulfuric acid, phosphoric acid, boric acid, BE, propionic acid, toluenesulfonic acid, methanesulfonic acid, and organic salts, and examples of alkalis include sodium hydroxide, potassium carbonate, and hydrogen carbonate. Examples include common inorganic bases and organic bases such as sodium, phosphoric acid/potassium hydride, and organic amines.

Alternatively, buffer solutions with the above acid-base combinations may be mentioned, such as phosphoric acid/potassium hydrogen-phosphoric acid, sodium acetate/acetic acid, sodium acetate/phosphoric acid, phthalic acid/potassium carbonate, phosphoric acid/potassium hydrogen/hydrochloric acid. , potassium dihydrogen phosphate-potassium hydrogen carbonate, succinic acid-sodium hydrogen carbonate, and the like.

In general, it is more preferable to avoid strong acids such as hydrochloric acid and hydrobromic acid, and strong alkalis such as caustic soda and caustic potash, as the alkali or alkali used for pH adjustment.

The reaction temperature is arbitrary between 0 and 200°C, but preferably 2
The temperature is 0 to 160°C.

Through this rearrangement reaction, the 8-hydroxy-4-cyclobentenone derivative represented by the general formula (I) and the general formula (It
) A cyclobentenone derivative consisting of a mixture with a 4-hydroxy-2-cyclobentenone derivative shown in be able to.

For example, in order to increase the production ratio of 8-hydroxy-4-cyclobenzonone derivative (1), the reaction pH should be adjusted to 8.
．． This is done by setting a relatively low value such as 5 to 4.5, or by suppressing the reaction conversion rate, while increasing the production ratio of 4-hydroxy-2-cyclopentenone The form (■). In order to convert 8-hydroxy-4-cyclobenzonone derivative CI) to 4-hydroxy- 2-cyclobentenone!
It is carried out by proceeding with an isomerization reaction to the 4-isomer (n).

In addition, 4-hydroxy-2-cyclobentenone derivative (T
In order to obtain only 1), when the raw material furancarbinol Tsuruhashi compound (1X) disappears in the rearrangement reaction, the reaction pH is made neutral or weakly alkaline, and the reaction is further reduced to 8-
It can be obtained by crystallizing hydroxy-4-cyclopentynone Gm form (I).

From the reaction mixture thus obtained, extraction, separation, concentration,
A cyclobentenone derivative consisting of the above mixture can be obtained by a general distillation operation.

Such a mixture can be used as it is, but if necessary, both aW forms can be separated and used by branching means such as column chromatography.

<Effects of the Invention> Thus, according to the method of the present invention, 8-hydroxy-4-cyclobentenone derivative (1) and 4-hydroxy-2-cyclobentenone derivative (II) can be obtained from furancarbinol derivative (III). A cyclobentenone derivative conductor consisting of a mixture with can be obtained industrially easily and in high yield.

Example The present invention will be explained below with reference to Examples.

Example 1 α-(ω
-Methoxycarbonylhexyl)furfuryl alcohol 91.25' (0,879 mot, for which 40
86501 parts by weight of water and 1780 parts by weight (86501 parts by weight)
3,05') P with potassium hydrogen and phosphoric acid
A buffer aqueous solution adjusted to L14.2 is charged, and heating and stirring are continued at 100° C. under a nitrogen atmosphere until the raw material is exhausted.

After the reaction was completed, the reaction mixture was cooled, extracted twice with methyl isobutyl ketone 6001, separated, and methyl isobutyl ketone was distilled off from the resulting organic layer to give 8-hydroxy-
2-(ω-methoxycarbonylhexyl)-4-cyclobentenone (I-1) and 11-hydroxy-2-(ω-
78.55' (yield 80.6%) of a mixture of methoxycarbonylhexyl)-2-cyclobentenone (II-1)
)Obtained. The generation ratio of (knee 1) and (n-1) is 8:
It was 1.

Example 2 α-(
ω-methoxycarbonylhexyl)furfuryl alcohol57. O? (0,287 mol), 50 times more than this! part (2850t) of water and L/10 parts by weight (5
, 751-) with sodium acetate and acetic acid.
Prepare a buffer aqueous solution adjusted to 100% under nitrogen atmosphere.
Continue heating and stirring at ℃ until all the raw materials are used up, and then
Continue the time reaction.

After the reaction was completed, the reaction mixture was cooled, extracted twice with methyl isobutyl ketone 500i, and separated once, and the obtained tea
8-hydroxy-2-(ω-methoxycarbonylhexyl-4-cyclobentenone Cl-1) and 4-hydroxy-2-(ω-
A mixture of 4!3.65' (yield 76.5
%)Obtained. Note that the production ratio of Cl-1) and (IT-1) was 2:5.

Example 8 α-(
ω-methoxycarbonylfurfuryl alcohol (60.1PC0,250 mol), 1 part by weight (2400F) of 40 times the weight of water and 1!10 times the redundant part (6,
A buffer aqueous solution adjusted to pH 5 with sodium acetate and acetic acid of 05') is charged, and heating and stirring are continued at 100° C. under a nitrogen atmosphere until 80% of the raw materials are consumed.

After the reaction is completed, the reaction mixture is cooled, extracted twice with methyl isobutyl ketone 5002 and separated, and methyl isobutyl ketone is distilled off from the resulting organic layer to obtain an oily substance. This was separated and purified by silica gel column chromatography (solvent: hexane-ethyl acetate) to produce 8-hydroxy-2-(cu-methoxycarbonylhexyl)-4.
-Cyclobentenone (nee 1) 84.9P (yield 58%)
) and 4-hydroxy-2-(ω-methoxycarbonylhexyl)-2-cyclobentenone (n-1) (yield 8
．． 8%) respectively.

Example 4 Same as Example 1 except that 2-(ω-methoxycarbonylbutyl)furfuryl alcohol 78.5F (0.85 mol) was used instead of α-(ω-methoxycarbonylhexylfurfuryl alcohol) After reaction and post-treatment, 8-
Hydroxy-2-(ω-methoxycarbonylbutyl)-
4-cyclobentenone (I-2) and 4-hydroxy-2
A mixture of -(ω-methoxycarbonylbutyl)-2-cyclobentenone (π-2) 62.4) (yield 84%) was obtained.

Note that the production ratio of Cl-2) and (I[-2) was 8:1.

Example 5 The reaction and post-treatment were carried out in the same manner as in Example 1, except that α-(ω-hexyloxycarbonylhexyl)furfurino alcohol was used instead of a-(ω-methoxycarbonylhexyl)furfuryl alcohol. , 8-hydroxy-2-(ω-hexyloxycarbonylhexyl)-4-cyclobentenone Cl-8) and 4-hydroxy-2-(ω-hexyloxycarbonylhexyl)-
A mixture of 2-cyclobentenone (n-8) is obtained.

Claims (1)

[Claims] Represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and n represents an integer of 4 to 8.) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ and ▲ Mathematical formulas, chemical formulas, tables, etc. are available. A cyclopentenone derivative which is a mixture of an 8-hydroxy-4-cyclopentenone derivative and a 4-hydroxy-2-cyclopentenone derivative represented by Manufacturing method