JPH0720913B2 - Process for producing optically active 4-hydroxy-2-cyclopentenones - Google Patents

Description

TECHNICAL FIELD The present invention relates to a method for producing optically active 4-hydroxy-2-cyclopentenones. More specifically, the present invention optically resolves a compound in which a hydroxyl group at the 4-position of 4-hydroxy-2-cyclopentenone of a mixture containing a racemate or one of the optical isomers in excess is protected to give an optically active 4-hydroxy compound. −
It relates to a method for producing 2-cyclopentenones.

According to such a production method, an optically active 4-hydroxy-2-cyclopentenone, which is an intermediate for the production of various pharmaceuticals including prostaglandins having various pharmacological actions, can be efficiently obtained in high yield. Moreover, such a production method is a production method which is extremely significant in terms of stereochemistry.

<Prior Art> Optically active 4-hydroxy-2-cyclopentenones have been reported in various production methods due to their high usefulness. For example, (1) diacetoxycyclopent-1-ene obtained from cyclopentadiene is hydrolyzed with an enzyme to give 3
(R) -acetoxy-5 (R) -hydroxycyclopent-1-ene is obtained, which is then oxidized with manganese dioxide to give 4 (R) -acetoxycyclopent-2-ene-1.
-Method for producing one (tetrahedron, 32 , 1713-171
8 (1977), tetrahedron, 32 , 1893 (1977)) (2) D or L-D or L derived from tartaric acid in four steps
By reacting -1,4-diiodo-2,3-isopropylidenedioxybutane with a lithio compound (R) or (S) -4-
Method for producing hydroxy-2-cyclopentenone (see Tetrahedron Letters, 10 , 759-762 (1976)) (3) 4 (R) -acetoxy-2 in 5 steps from terrain
-Method for producing cyclopentenone (tetrahedron
Letters, 29, derived from 2553-2556 (1978)) (4) 2,4,6-chlorophenol 3,5,5
-Trichloro-1,4-dihydroxycyclopent-2-
Method for optically resolving ene-1-carboxylic acid and further producing (R) -4-t-butyldimethylsiloxycyclopent-2-enone in four steps (see Tetrahedron Letters, 1539-42 (1979)). (5) 1-Cyclopentene-3,5-dione is asymmetrically reduced by a chiral binaphthol compound and lithium aluminum hydride modified with an alcohol to obtain (R) or (S) -4-hydroxy-2-cyclopentenone. (See JP-A-56-123932) (6) dl-4-hydroxy-2-cyclopentenone is combined with an optical resolving agent to separate as a diastereomer,
Thereafter, the resolving agent is removed to produce an optically active 4-hydroxy-2-cyclopentenone (JP-A-57-15).
(See No. 9777) (7) Lead the half-ester form of orthophthalic acid of dl-4-hydroxy-2-cyclopentenone into a salt of an optically active amine and recrystallize to obtain the optically active substance. Method for producing active 4-hydroxy-2-cyclopentenone (see JP-A-57-14560) (8) Optical resolution by optically resolving by utilizing asymmetric discrimination ability of polysaccharide derivative Method for producing 4-hydroxy-2-cyclopentenone (see JP-A-61-267536) (9) E-3-hydroxy-5-trimethylsilyl-4
3 from n-butyl pentenoate by asymmetric epoxidation
A method for producing (R) -4-t-butyldimethylsiloxy-2-cyclopentenone through 6 steps such as obtaining (R) form and iodolactonization and intramolecular cyclization (Chemical Society of Japan, 58th Spring) Proceedings of Annual Meeting p2008) (10) dl-4-hydroxy-2-cyclopentenone
[(S) -binap] (OCOCH 3) 2 or Ru [(R) -bina
p] (OCOCH ₃ ) ₂ in the presence of a catalyst to cause an optically active 4-hydroxy-
Method for producing 2-cyclopentenone (JP-A-64-6228)
(11) A method of separating a 4-hydroxy-2-cyclopentenone derivative from an optically active binaphthol or its derivative as a crystalline complex, and then separating from the complex (see JP-A-1-125340) (11) A method of separating a 4-hydroxy-2-cyclopentenone derivative from an optically active binaphthol or its derivative as a crystalline complex, and then separating from the complex (see JP-A-1-125340).

These methods use harmful substances ((1),
(4)), using starting materials that are not easily available ((3), (5)), using optical resolving agents that are not easily available ((6), (10), (11)), high optical Purity cannot be obtained ((2), (7)), the process is long and economically difficult ((9)), and they have their respective disadvantages, so it cannot be said that the process is truly industrial. . In addition, the method (8) can provide a 4-hydroxy-2-cyclopentenone derivative having a high optical purity in a short step, but the chiral discrimination ability is not sufficient, so that it is not possible to supply this important intermediate at low cost. .

<Object of the Invention> As described above, the conventional production method of optically active 4-hydroxy-2-cyclopentenones is not necessarily industrially excellent.

Therefore, the present inventors have made industrially advantageous 4-hydroxy-2
-As a result of intensive research to find out a method for producing cyclopentenones, an optically active carbamate derivative of amylose has an extremely high asymmetric discrimination ability with respect to a mixture of optical isomers of 4-hydroxy-2-cyclopentenones. Therefore, the present invention has been found to be advantageous for optical resolution and has reached the present invention.

<Structure of Invention> That is, the present invention has the following formula [I]: [In the formula, R represents a protective group for a hydroxyl group. ] The following formula [II] characterized in that 4-hydroxy-2-cyclopentenone represented by the formula: is optically resolved by using an optically active carbamate derivative of amylose. [In the formula, R is the same as the above definition. * Represents an asymmetric carbon atom in which optical activity was induced. ] It is a manufacturing method of optically active 4-hydroxy-2- cyclopentenones represented by these.

4-hydroxy-of the formula [I] used in the present invention
In 2-cyclopentenones, R is a protective group for a hydroxyl group. As the protecting group, -SiR ₁ R ₂ R ₃ (wherein R ₁ , R ₂ and R ₃ are the same or different and are C _{1 to} C ₆ hydrocarbon groups), a group that forms an acetal bond with the oxygen atom of the hydroxyl group. , Or an acyl group. Examples of R ₁ , R ₂ and R ₃ of —SiR ₁ R ₂ R ₃ include methyl, ethyl, isopropyl, t-butyl and phenyl groups. Among them, preferable examples of -SiR ₁ R ₂ R ₃ include t-butyldimethylsilyl, t-butyldiphenylsilyl and methyldiphenylsilyl.

Examples of the group that forms an acetal bond with the oxygen atom of the hydroxyl group include methoxymethyl, 1-ethoxyethyl, (2-methoxyethoxy) methyl, and tetrahydropyranyl groups. Examples of the acyl group include acetyl, propionyl, n-butyryl, iso-
Butyryl, n-valeryl, caproyl, benzoyl and the like can be mentioned.

Examples of the optically active carbamate derivative of amylose used in the present invention include amylose tris (S) -1-phenylethyl carbamate, amylose tris (R) -1-phenylethyl carbamate, amylose tris (S) -1- (1- Naphthyl) ethyl carbamate, amylose tris (R) -1- (1-
Examples thereof include naphthyl) ethyl carbamate, and amylose tris (S) -1-phenylethyl carbamate is particularly preferable. The optically active carbamate derivative of amylose can be easily obtained by reacting amylose with an optically active isocyanate.

In the present invention, such an optically active carbamate derivative of amylose is used to prepare 4-hydroxy-2- of the formula [I].
The specific means and method for optically resolving cyclopentenones are not limited, and any known means and method may be adopted. For example, the exemplified amylose derivative is supported on silica gel, alumina, cellulose or the like, preferably silica gel which has been subjected to usual silylation treatment (for example, treatment with 3-aminopropyltrimethoxysilane etc.), and this is packed in a column, and hexane or dichloromethane is added. , A non-polar solvent such as chloroform, benzene, or toluene; a polar organic solvent such as methanol, ethanol, propanol, 2-propanol, or ethyl acetate; a mixed solvent thereof; or a solvent of the formula [I] containing water. Optical resolution can be carried out by subjecting 4-hydroxy-2-cyclopentenones to a column treatment.

As described above, an optically active 4-hydroxy-2-cyclopentenone that can be a synthetic intermediate of various prostaglandins can be efficiently produced with a higher optical yield than an easily available racemate. You can

<Effects of the Invention> The feature of the method of the present invention is to utilize the asymmetric discrimination ability of the optically active carbamate derivative of amylose. For example, 4-hydroxy-2-cyclopentenones are converted into R-form and S-form by liquid chromatography or the like. Of optical isomers. It is superior to the conventional manufacturing method in the following points. Easy to operate (separation by liquid chromatography). In the case of a racemate, each optical isomer can be obtained in a yield close to 50% of the theoretical yield. The optically resolved 4-hydroxy-2-cyclopentenones can be directly used as synthetic intermediates for various prostaglandins. Further, since it has a remarkably high asymmetric discrimination ability as compared with the optical resolution method using a polysaccharide derivative such as cellulose, the treatment capacity of separation is dramatically improved, and the production cost can be greatly reduced.

<Example> Hereinafter, an example of the present invention will be described in more detail.

Example 1 Large pore silica gel obtained by treating amylose tris (S) -1-phenylethyl carbamate with 3-aminopropyltrimethoxysilane (particle diameter 7 to 10 μm, pore diameter 1000 to 4000).
A chiral stationary phase was prepared by loading 25 wt% of Å) onto a column having a length of 25 cm and an inner diameter of 0.46 cm. Hexane
Using 2- / 2-propanol (98/2) as an eluent, 4-t-butyldimethylsilyloxy-2-cyclopentenone (racemate) was passed through the above column at 25 ° C at a flow rate of 0.5 ml / min. JASCO TRIROTARII was used as the chromatograph, and JASCO UV-100-III (wavelength 23
0nm), JASCO DIP-181C (wavelength 36
5 nm) was used for optical resolution. The elution pattern obtained is shown in FIG. As is apparent from FIG. 1, the (+) form was eluted first by the optical resolution of the present invention, and then the (-) form was eluted.
It can be seen that the body elutes. The (-) form eluted later was ▲ [α] ²¹ _D ▼ -67.0 ° (C = 1.0, methanol) at S
It is the body. In addition, the (-) body eluted later was ▲ [α] ²¹ _D ▼
It is an R form at + 67.0 ° (C = 1.0, methanol).

Example 2 4-t-butyldiphenylsilyloxy-2-cyclopentenone (yasemic body) was optically resolved in the same manner as in Example 1. However, the eluent composition was hexane / 2-propanol (9/1). The elution pattern obtained is shown in FIG. As is apparent from FIG. 2, the (+) form is eluted first (S form) and the (−) form is subsequently eluted (R form) by the optical resolution of the present invention.

Example 3 4-Methyldiphenylsilyloxy-2-cyclopentenone (racemate) was optically resolved in the same manner as in Example 2. The elution pattern obtained is shown in FIG. As is apparent from FIG. 3, the (+) form is eluted first (S form) and the (−) form is eluted (R form) by the optical resolution of the present invention.
I understand.

Example 4 4-Acetyloxy-2-cyclopentenone (racemate) was optically resolved in the same manner as in Example 2. The elution pattern obtained is shown in FIG. As is clear from FIG. 4, the (+) form was eluted first by the optical resolution of the present invention (R
It can be seen that the body), and subsequently the (−) body is eluted (S body).

[Brief description of drawings]

Each figure shows the elution pattern of 4-hydroxy-2-cyclopentenones (racemate) when amylose tris (S) -1-phenylethylcarbamate was used. FIG. 1 shows the elution pattern of 4-t-butyldimethylsilyloxy-2-cyclopentenone (Example 1). Fig. 2 shows 4-t-butyldiphenylsilyloxy-2-
3 shows the elution pattern of cyclopentenone (Example 2). FIG. 3 shows the elution pattern of 4-methyldiphenylsilyloxy-2-cyclopentenone Example 3). FIG. 4 shows the elution pattern of 4-acetyloxy-2-cyclopentenone (Example 4). In these figures, the horizontal axis represents time. Also, in the chromatographs in each figure, the upper column shows JASCO DIP.
The optical rotation measured at a wavelength of 365 nm using a -181C polarimeter is shown. The upper side of the baseline shows (+) optical rotation and the lower side shows (-) optical rotation. The bottom is JASCO UV-100-III
The UV absorption measured with a UV detector at a wavelength of 230 nm is shown. The peaks that are detected only by the UV detector and not by the polarimeter indicate optically inactive impurities such as silanol derivatives.

Claims (3)

[Claims] 1. The following formula [I]: [In the formula, R represents a protective group for a hydroxyl group. ] The following formula [II] characterized in that 4-hydroxy-2-cyclopentenone represented by the formula: is optically resolved by using an optically active carbamate derivative of amylose. [In the formula, R is the same as the above definition. * Represents an asymmetric carbon atom in which optical activity was induced. ] The manufacturing method of optically active 4-hydroxy-2- cyclopentenone represented by these. 2. In the above formulas [I] and [II], the protecting group for R is --SiR ₁ R ₂ R ₃ (wherein R ₁ , R ₂ and R ₃ are the same or different and are C _{1 to} C ₆ hydrocarbons). Group), a group forming an acetal bond together with an oxygen atom of a hydroxyl group, or an acyl group, The method for producing an optically active 4-hydroxy-2-cyclopentenone according to claim 1. 3. The optically active 4-hydroxy-2-cyclopentenone according to claim 1 or 2, wherein the optically active carbamate derivative of amylose is amylose tris (S) -1-phenylethylcarbamate. Manufacturing method.