JPS60199848A - Production of optically active 4-hydroxy-2- cyclopentenone - Google Patents

Abstract

PURPOSE:To obtain a reaction mixture containing an optically active isomer in excess to its antipode, and to obtain the objective optically active isomer, by reacting a lactone with 4-hydroxy-2-cyclopentenone at a specific molar ratio in the presence of a specific catalyst. CONSTITUTION:4-Hydroxy-2-cyclopentenone is made to react with a lactone selected from (1R,5S)-6,6-dimethyl-4-hydroxy-3-oxabicyclo[3,1,0]-hexan-2-one and (1S,5R)-6,6-dimethyl-4-hydroxy-3-oxabicyclo[3,1,0]hexan-2-one at a molar ratio of 1.5-2:1 in the presence of p-toluenesulfonic acid or benzene toluencesulfonic acid in an azeotropic solvent under azeotropic dehydration. A reaction mixture containing either one of the optically active isomers in excess to its antipode can be produced by this process. The mixture is crystallized to obtain the optically active isomer, which is hydrolyzed in an aqueous solution to obtain an optically active 4-hydroxy-2-cyclopentenone.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing optically active 4-hydroxy-2-cyclobentenone.

Optically active 4-hydroxy-2-cyclopentenone is a very useful chemical compound as an intermediate for medicine and agricultural chemicals. For example, 4-hydroxy-2-cyclopentenone is a PG compound.
E2. It is used as a raw material for prostaglandins such as PGF2-α.

As a method for obtaining such optically active 4-hydroxy-2-cyclobentenone, for example, JP-A-57-1597
A method described in Japanese Patent No. 77 is known.

In this method, lactones and 4-hydroxy-2-cyclobentenone are reacted at a molar ratio of 1:1.2 to 1.8, and one of the optically active substances is separated and then hydrolyzed.

By the way, the same publication describes, for example, 4-hydroxy-2-cyclobentenone and (IR, 58)-6,6-dimethyl-4-hydroxy-8-oxabicyclo(8,1,0)bexan-2-one. obtained when reacting (IR
,58)-6,6-dimethyl-8-oxa-4(R)
-(1(R) -4-oxo-2-cyclopentenyloxy]bicyclo(i3.1.0)hexan-2-one(
(hereinafter referred to as Cl-11)) and (IR,58)-6,6-
cymethyl-8-oxa-4(R)-(1(S)-4-oxo-2-cyclopentenyloxy]bicyclo(8,1
, 0) There is no description of the production ratio of cyclobentenone ethers of hexan-2-one (hereinafter referred to as (1-b)), and judging from the example in which this mixture is separated by column chromatography. However, the CI--)/(1-b) ratio when using this method is quite low, and therefore, the isolation of optically active substances from such mixtures has no choice but to rely on chromatographic purification. , requires very complicated operations.

Furthermore, since the subsequent hydrolysis reaction is carried out using a mixed solution of water and a water-soluble organic solvent such as water-dioxane, there are also problems with post-treatment and purification after the reaction is completed, making it difficult to manufacture industrially. It was unsatisfactory.

For these reasons, the present inventors have improved the problems of the above-mentioned method, and have developed an optically active 4-hydroxy-2
- As a result of studies to produce cyclobentenone, it was found that either one of the above lactones and 4-hydroxy-2-cyclobentenone could be reacted at a specific reaction molar ratio and in the presence of a specific catalyst. It is possible to obtain a reaction mixture containing an excess amount of the optically active form with respect to its enantiomer, and as a result, it is very easy to isolate the optically active form by the crystallization method, and furthermore, the subsequent hydrolysis reaction is also easy. , can be easily carried out using only water without any need for organic solvents, etc., and the objective optically active 4-hydroxy-2-cyclobentenone can be obtained extremely advantageously through this series of processes. They discovered this and completed the present invention.

That is, the present invention provides 4-hydroxy-2-cyclobentenone and (IR,58)-6,6-dimethyl-4-hydroxy-3-oxabicyclo(8,1,0)hexane-2
-one or (IS, 5R)-6,6-cymethyl-4
-Hydroxy-3-oxabicyclo(8,1,0)hexan-2-one lactones, 4-hydroxy-2-
Cyclobentenone is used in a molar amount 1.5 to 2 times that of the lactone, and reacted with azeotropic dehydration in an azeotropic solvent in the presence of para-toluenesulfonic acid or benzenetoluenesulfonic acid (IR, 58). -6,6-cymethyl-3
-oxa-4(R)-(1(R)-4-oxo-2-cyclopentenyloxy]bicyclo(a,i.

0] Hexan-2-one or (IS, 5 liters)-6,
6-dimethyl-8-oxa-4(S)-(1(8)-4
-oxo-2-cyclopentenyloxy]bicyclo(8
, 1,0) cyclobentenone ethers containing hexane-2-one in an excess amount relative to each enantiomer were obtained, and this was crystallized to form (IK, 58)-6,6-dimethyl-8
-Oxa-4(R) -(1(Ill) -4-oxo-2-cyclopentenyloxy]bicyclo[8°1.0
]Hexan-2-one or (1s.

5R)-6,6-dimethyl-3-oxa-4(S) -
Optically active 4-hydroxy, characterized in that C1(S) -4-oxo-2-cyclopentenyloxy]bicyclo(8,1,0)hexan-2-one is isolated and then hydrolyzed in an aqueous solution. A method for producing -2-cyclobentenone is provided.

The present invention will be explained in detail below.

In the reaction between 4-hydroxy-2-cyclobentenone and lactones, the reaction molar ratio of the two is very important; 4-hydroxy-2-cyclobentenone is 41.5 ~2 times the mole is used, most preferably around 1.7 times the mole.

With this molar ratio, for example, the generated (,1-8)/CI-b
) ratio relationship was first clarified by the present inventors, and is also shown in Figure 1.

4-hydroxy-2-cyclobentenone/lactone-1
, 5-2/l (molar ratio) only if Cl7a)/(
1-b,) ratio is specifically improved, and outside this molar ratio range, the excess rate decreases, which is not preferable.

As the catalyst, para-toluenesulfonic acid or benzenetoluenesulfonic acid is used, and their pyridine salts are unfavorable, for example, in view of the produced [■-,)/[1-b] ratio.

The amount of the catalyst used is 0.01 to 0.5 times equivalent, preferably 0.05 to 0.3 times equivalent, relative to the lactone.

As the reaction solvent, a so-called azeotropic solvent that is azeotropic with water is used, and representative examples include benzene and toluene.

Since this reaction is a condensation reaction that produces water, it is necessary to proceed while the produced water is removed from the reaction system by azeotroping with the azeotropic solvent. At this time, the azeotropic solvent distilled off together with the water can be returned to the reaction system after separation from the water.

The reaction temperature is a temperature at which the azeotropic solvent can be azeotroped with water, and is usually 60 to 120°C, preferably 60 to 115°C.

The reaction time varies depending on various conditions and is not limited in any way, but is generally 2 to 7 hours.

Thus, for example, (IR, 5
8) When -6,6-dimethyl-4-hydroxy-8-oxabicyclo(8,1,0)hexan-2-one is used, C1-a) containing an excess amount of (1--) (1
-b) (7) mixture is obtained and (IS,5R)-6
,6-dimethyl-4-hydroxy-3-oxabicyclo(8,1,0)hexan-2-one, an excess of (18,5R)-6°6-dimethyl-8-oxa- ('I −
d) and (18,5R)-6,6-dimethyl-8-oxa-4(8)-(1(R)-4-oxo-2-cyclopentenyloxyfubicyclo(+3.1.0)hexane-
A mixture of 2-ones (hereinafter referred to as (1-e)) is obtained.

(1-8) or CI-d] in the above mixture
-b) or [lc] is higher than the excess in the mixture obtained by the method specifically disclosed in JP-A-57-159777, and (
This method is not only very advantageous as a method for producing 1-a) or 01-d), but also allows for the separation of each by a very easy separation operation.

That is, from these mixtures (1-a) or (1
-d) can of course be separated individually by column chromatography, but since the excess rate is high, the general separation method of crystallization from a mixture does not require such complicated operations. easily (1-
a] or (1-d) can be separated with high purity.

The separation operation by crystallization uses toluene as the crystallization solvent,
Common solvents such as ethyl acetate, hexane, isopropyl ether, alone or in mixtures, are used.

The crystallization method itself does not require any special method; for example, the above mixture is dissolved in a crystallization solvent, and if necessary, (1-
-) or [1-d') seed crystals may be added and crystallization treatment may be performed according to a conventional method.

The amount of solvent is also selected appropriately depending on each condition.
Although not particularly limited, it is generally 0.8 to 10 times the weight of the mixture.

The crystallization temperature is also appropriately determined depending on conditions such as the type and amount of the solvent used, but is generally in the range of -200C to 90C.

In addition, during crystallization, C1- in each mixture
It is preferable to crystallize an amount commensurate with the excess of a) or CI-d) in terms of the purity of the obtained (1-&J or (1-d)).

If necessary, the crystals obtained here can be purified by a method such as recrystallization using the above-mentioned solvent.

Hydrolysis of separated optically active forms such as (1-6) or (1-d) produces optically active 4-hydroxy-2
- Considering the stability of cyclobentenone, it is preferable to carry out the reaction under neutral conditions.

In addition, considering post-treatment and purification after hydrolysis, it is preferable to use as little organic solvent as possible, and usually (1-
This is carried out by heating a) or (1-d) in 2 to 20 times the weight of water.

The reaction temperature is usually 50-100°C1, preferably 60-1
00°C, and the reaction time is not particularly limited.

By this method, optically active 4-hydroxy-2-cyclobentenone can be easily obtained in a good yield.

After completion of the reaction, separation of lactones and optically active 4-hydroxy-2-cyclobentenone from the reaction mixture is as follows:
For example, the reaction solution may be cooled as it is, or it may be concentrated and then cooled, and the precipitated lactones may be separated in a furnace.
Concentrate the liquid to obtain the desired optically active 4-hydroxy-2
- by obtaining cyclobentenones. If necessary, such optically active 4-hydroxy-2-cyclobentenone can be purified by chromatography or distillation.

Thus, according to the method of the present invention, optically active 4-hydroxy-2-cyclobentenone can be obtained industrially easily and in good yield.

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

Example 1 4-Hydroxy-2-cyclobentenone 1
9.62y (200 mmol), (IR,58)-6,
6-dimethyl-4-hydroxy-3-oxabicyclo(
8,1,0) hexan-2-one 16.76f (118
0.449 mmol), p-toluenesulfonic acid, and 160 ml of benzene, and the mixture was heated to reflux.

The reaction is allowed to proceed for 4 hours while the produced water is azeotropically taken out of the reaction system. After the reaction is completed, 80 g of water is added and the organic layer is separated. The organic layer is further washed with 60 ml of 8% sodium chloride water and 70 ml of water. The organic layer was concentrated under reduced pressure to give (IR,5S)-6,,6-dimethyl-8-oxa-
4(Ill)-(10%)-4-oxo-2-cyclopentenyloxy]bicyclo(8,1°0]hexane-2
-on (1-a) and (1 liter).

58)-6,6-dimethyl-8-oxa-4(R) -
C1(S) -4-oxo-2-cyclopentenyloxy]bicyclo(8,1,0)hexan-2-one(1-
A mixture of b) 25.021 is obtained.

Dissolve 1 fM of the above mixture in 10 ml of ethyl acetate,
After adding 6 ml of hexane at ℃, slowly cool to 25℃.
(1 liter, 5S) 6,6-cymethyl-8-oxa-4
(R) -C1(R) -4-oxo-2-cyclopentenyloxy]bicyclo(8,1,0)hexane-2-
Inoculate 10# of On (1-a) as a seed crystal. Cool further and keep warm at 0°C for 8 hours. When cold, filter (1
-a) 8.521 crystals are obtained.

α)%'-44,9° (C=1.methanol) m, p
, 90° C. Next, Cl-8)8F is heated with water 1011 at 75° C. for 8 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to remove 4 ml of the main stock, cooled to 0°C, and heated to 8 ml.
Hold time. The precipitated crystals (lactones) are separated from each other and p
Concentrate the liquid further. The concentrated residue was purified by chromatography to obtain 1.25 g of 4 (R)-hydroxy-2-cyclobentenone.

α) AO+ 96° (C=1.methanol) Example 2 Into the same apparatus as used in Example 1, 4-hydroxy-2
-cyclobentenone 28.15 F (286 mmol), (IR,58) -6.

6-dimethyl-4-hydroxy-8-oxabicyclo(
8,1,0) hexan-2-one 16.76f (118
millimoles), 0.44f of paratoluenesulfonic acid, and 160d of hidruene, and the mixture was heated to reflux. The reaction is allowed to proceed for 4 hours while the produced water is azeotropically taken out of the reaction system.

After the reaction is completed, post-treatment and purification are carried out according to Example 1. (
IR, 58)-6,6-dimethyl-8-oxa-4(R
) -(1(R) -4-oxo-2-cyclopentenyloxyfubicyclo(8,1,0)hexan-2-one and (IR,58)-6,6-dimethyl-8-oxa-4
25.821 of a mixture of (R)-C1(S)-4-oxo-2-cyclopentenyloxyfubicyclo(8,1,0)hexan-2-one is obtained.

The (1-a:]/(1-b) ratio was 1.72.

The above mixture 15F was dissolved in 15 g of ethyl acetate, and 45
After adding 15 g of hexane to the mixture, the mixture was slowly cooled at 0° C., kept at 0° C. for 4 hours, and the precipitated crystals were filtered to obtain crystals 4.1y of C7-a).

Next, this crystal 4f was mixed with petroleum ether: ethyl acetate = 10
: Heat and dissolve in 80 wrt of a mixed solution of 1. After that, it was slowly cooled and kept at 0°C for 2 hours, and the precipitated crystals were allowed to pass through.
8.57 Fl of crystals of (1-11) are obtained.

α〕9° -45,2° (c=1.methanol)m-
P, 90-91°C Next, Ko(7)(1-&':)81 is heated with 10*l of water at 70°C for 4 hours. Thereafter, the product is post-treated and purified according to Example 1 to obtain 1.249 of 4 (R)-hydroxy-2-cyclobentenone.

α), +97.5° ((+=1.ethanol)n” 1
．． 5085 Example 3 Converting paratoluenesulfonic acid to benzenesulfonic acid 0.4f
The reaction and post-treatment were carried out in the same manner as in Example 1 except that (
IR,5S)-6,6-dimethyl-8-oxa-4(几)-(1(R)-4-oxo-2-cyclopentenyloxyfubicyclo(8,1,0)hexan-2-one(
:l-8) and (IR,58)-6,6-cymethyl-8-
25.081 of a mixture of oxa-4(几)-(1(S)-4-oxo-2-cyclopentenyloxyfubicyclo(8,1,0)hexan-2-one [I-b) is obtained.

Ta.

Dissolve 15 g of the above mixture in 18+Il/ethyl acetate,
Add 12 liters of hexane at 50°C, cool slowly,
(IR, 5S) -6,6-dimethyl-8-oxa-4(R) -(1(R)-4-oxo-2-cyclopentenyloxyfubicyclo(8,1,0)hexane- 10IIy of 2-one crystals are inoculated as rice crystals. After further cooling and keeping at 10°C for 5 hours, the precipitated crystals are filtered to obtain 8.06 fft of (i-8) crystals.

Next, add this (1-8)8N to 80% water with 10+w/
Heat at °C for 1 hour. Thereafter, the product is post-treated and purified according to Example 1 to obtain 1.22 f of 4 (R)-hydroxy-2-cyclobentenone.

α):'+96.4℃ (c = l, ethanol)

[Brief explanation of drawings]

Figure 1 shows the raw material 4-hydroxy-2-cyclobentenone/lactones (molar ratio) when reacting with para-toluenesulfonic acid as catalyst W.

Claims (1)

[Claims] 4-hydroxy-2-cyclobentenone and (IR, 58
)-6,6-dimethyl-4-hydroxy-8-oxabicyclo[8,1,0] hexan-2-one or (
IS, 5)-6゜6-dimethyl-4-hydroxy-8
- Lactones of oxabicyclo(8,1,0)hexane-2-one are mixed with 1.5 to 2 times the mole of 4-hydroxy-2-cyclobentenone relative to the lactones, and paratoluenesulfonic acid is used. Alternatively, in the presence of benzene-toluenesulfonic acid, the reaction is carried out with azeotropic dehydration in an azeotropic solvent (
1 liter, 5S)-6゜6-dimethyl-8-oxa-4(R
) -CI (R)-4-oxo-2-cyclopentenyloxy]bicyclo(8,1,0)hexan-2-one or (18,5R)-6,6-cymethyl-8-oxa-4(8) -(1(S)-4-oxo-2-cyclopentenyloxy]bicyclo(8,1゜0)hexane-2-one in an excess amount relative to each enantiomer to obtain cyclobentenone ethers, This was obtained by crystallization method (I
R,58)-6#6-cymethyl-8-oxa-4(R)
-(1(几)-4-oxo-2-cyclopentenyloxy]bicyclo(8,1,0)hexan-2-one or (18,5几)-6,6-dimethyl-3-oxa-
4(8) -(1(S)-4-oxo-2-cyclopentenyloxy)bicyclo(8,1°0]hexane-2
A method for producing optically active 4-hydroxy-2-cyclobentenone, which comprises isolating -one and then hydrolyzing it in an aqueous solution.