JPH0324032A - Production of optically active 4-hydroxy-2-cyclopentenones - Google Patents

Abstract

PURPOSE:To produce the subject optically active compound in high efficiency and yield by carrying out optical resolution of 4hydroxy-2-cyclopentenones using an optically active carbamate derivative of amylose as an optical resolution agent. CONSTITUTION:Optically active 4-hydroxy-2-cyclopentenones can be produced from racemic 4-hydroxy-2-cyclopentenones of formula l (R is OH-protecting group) or a mixture of the compound containing either one of the optical isomers in excess by carrying out the optical resolution of the compound using an optically active carbamate derivative of amylose (especially preferably amylose tris(S)-1-phenylethyl carbamate, etc.) as a resolution agent. Since the optically active carbamate derivative of amylose has remarkably high asymmetry-recognition capability, the separation capacity is greatly improved and the production cost is remarkably reduced. The operation is simple and advantageous. The product is useful as a production intermediate for prostaglandin, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION Industrial Application Field The present invention relates to a method for producing optically active 4-hydroxy-2-cyclobentenones. More specifically, the present invention optically resolves a compound in which the 4-hydroxyl group of 4-hydroxy-2-cyclobentenone, which is a racemate or a mixture containing an excess of one of the optical isomers, is protected, and optically active 4-hydroxy −
The present invention relates to a method for producing 2-cyclopentenones.

According to this production method, it is possible to efficiently obtain optically active 4-hydroxy-2-cyclopentenones in high yield, which are intermediates for the production of various pharmaceutical products, including prostaglandins having various pharmacological actions. The manufacturing method that allows for the formation of a polymorphism is extremely significant in terms of stereochemistry.

Prior Art Various methods for producing optically active 4-hydroxy-2-cyclopentenones have been reported due to their high usefulness. For example, (1) diacetoxycyclobent-1-ene obtained from cyclobentadiene is hydrolyzed with an enzyme, and 3
A method for producing 4(R)-acetoxycyclobent-2-en-1-one by obtaining (R)-acetoxy5{R}monohydroxycyclobent-1-ene and then oxidizing it with manganese dioxide ( Tetrahedron, 32.1
713-1718 (1977), Tetrahedron, 32
．． 1893 (see 19771) (2) D or L derived from D or L monotartaric acid in 4 steps
-1. 4-jodo-2,3-impropylidenedioxybutane is reacted with a lithio compound to form (R) or (S
) - Method for producing 4-hydroxy-2-cyclopentenone (Tetrahedron Letters, March 759-7)
62 (1976)) (3) Method for producing 4{R}-acetoxy-2-cyclopentenone from terrain in 5 steps (Tetrahedron Letters, Gong, 2553
-2556 (see 1978>) (4) Optical analysis of 3,5.5-}lichloro-1,4-dihydroxybent-2-ene-1-carboxylic acid derived from 2,4.6-}lichlorophenol. divide,
A method for producing (R)-4-t-butyldimethylcyclobent-2-enone in four further steps (see Tetrahedron Letters, 1539-42 (19791)) (5) 1-cyclobentene-3. 5-Sion was asymmetrically reduced with a chiral binaphthol compound and alcohol-modified lithium aluminum hydride (R).
Or a method for producing (S)-4-hydroxy-2-cyclobentenone (see JP-A-56-123932) (61 dl-4-hydroxy-2-cyclopentenone and an optical resolving agent are combined to form a diastereoisomer. A method for producing optically active 4-hydroxy-2-cyclobentenone by separating it as a mer and then removing the resolving agent (JP-A-5
7-159777) <7) The half ester of orthophthalic acid of dl-4-hydroxy-2-cyclopentenone is converted into a salt of optically active amine, the optically active compound is obtained by recrystallization, and then deprotected. A method for producing optically active 4-hydroxy-2-cyclobentenone (see JP-A-57-14560) (8) Optical resolution using the asymmetric discrimination ability of polysaccharide derivatives. Method for producing active 4-hydroxy-2-cyclopentenone (see JP-A-61-267536) (9) E-3-hydroxy-5-trimethylsilyl-4
-3( by asymmetric epoxidation from n-butylbentenate)
A method for producing (R)-4-t-1-butyldimethylsiloxy-2-cyclopentenone by obtaining the R) compound and carrying out six steps such as iodolactonization and intramolecular cyclization. See conference proceedings p. 2008> (10) dl-4-hydroxy-2-cyclobentenone as Ru [(S)-binap] (OCOCH3)
2 or Ra [(R)-binapl (OCOC}T
3) A method for producing optically active 4-hydroxy-2-cyclopentenone by applying hydrogen and kinetically resolving it in the presence of the catalyst described in 2 (see JP-A No. 64-6228) (11) A method in which a 4-hydroxy-2-cyclopentenone derivative is formed into a crystalline complex with optically active binaphthol or a derivative thereof, and then separated from this complex (see JP-A-1-125340).

These methods use harmful substances ((1), (4)
), using starting materials that are not easily available ((3), +
51), using an optical resolving agent that is not easily available
6), (10), (11)), high optical purity cannot be obtained ((2), (7)), the process is long and economically difficult <+9)). Each method has its own shortcomings, so it cannot yet be said that it will become a truly industrial process. In addition, in method (8), 4-hydroxy-2- of high optical purity can be obtained in short steps.
Although cyclobentenone derivatives can be obtained, this important intermediate cannot be supplied at low cost due to insufficient asymmetric discrimination ability.

OBJECTS OF THE INVENTION As described above, conventional methods for producing optically active 4-hydroxy-2-cyclobentenones cannot necessarily be said to be industrially superior.

Therefore, the present inventors have developed an industrially advantageous 4-hydroxy-2
- As a result of intensive research to find a method for producing cyclobentenones, we found that the optically active rubamate derivative of amylose has an extremely high asymmetric discrimination ability for a mixture of optical isomers of 4-hydroxy-2-cyclobentenones. The inventors have discovered that this is advantageous for optical resolution, and have arrived at the present invention.

Structure of the Invention> That is, the present invention has the following formula [I] O [wherein R represents a hydroxyl group-protecting group]. The following formula [II] is characterized in that 4-hydroxy-2-cyclopentenones represented by the formula [II] are optically resolved using an optically active rubamate derivative of amylose [wherein R is the same as defined above]. * represents an asymmetric carbon atom in which optical activity is induced. ] This is a method for producing optically active 4-hydroxy-2-cyclobentenones represented by:

4-Hydroxy- of formula [I] used in the present invention
In 2-cyclopentenones, R is a hydroxyl protecting group. As a protecting group, -S I RI R2R3 (where R++ R2, R3 are the same or different, C1
~C6 hydrocarbon group>, a group that forms an acetal bond with the oxygen atom of a hydroxyl group, or an acyl group. One S
Examples of Q1, R2, and Ra in i RI R2 R3 include methyl, ethyl, improvil, t-butyl, and phenyl groups. Among these, -SIRIR2R3 is preferably t-butyldimethylsilyl, t-butyldiphenylsilyl, or methyldiphenylsilyl.

Examples of groups that form an acetal bond together with the oxygen atom of a hydroxyl group include methoxymethyl, 1-ethoxyethyl,
(2-methoxyethoxy>methyl, tetrahydropyranyl group, etc. can be mentioned. Examples of the acyl group include acetyl, probionyl, n-butyryl, iqo-butyryl, n-valeryl, cabroyl, benzoyl, etc. .

Examples of optically active rubamate derivatives of amylose used in the present invention include amylose tris (S
+-1-Phenylethyl Rubamate, Amylose Tris(R)-1-Phenylethyl Rubamate, Amylose Tris(S)-1-(1-naphthyl)ethyl Rubamate, Amylose Tris(R)-1-(1-naphthyl > Among these, amylose tris(S)-1-phenylethyl carbamate is particularly preferred. This optically active carbamate derivative of amylose can be easily produced by reacting amylose with an optically active isocyanate. can get.

In the present invention, using such an optically active rubamate derivative of amylose, 4-hydroxy-2-
The specific means and method for optically resolving cyclobentenones are not limited at all, and any known means or method may be employed.

For example, the exemplified amylose derivatives are supported on silica gel, alumina, cellulose, etc., preferably silica gel that has been subjected to a conventional silylation treatment (e.g., treatment with 3-aminoprobyltrimethoxysilane), and this is packed in a column, and then hexane, cellulose, etc. are supported. Nonpolar solvents such as dichloromethane, chloroform, benzene, and toluene; polar organic solvents such as methanol, ethanol, propanol, 2-probanol, and ethyl acetate; mixed solvents of these; or formulas using these solvents containing water. 4-hydroxy-
Optical resolution can be achieved by treating 2-cyclobentenones with a column.

As described above, optically active 4-hydroxy-2-cyclopentenones, which can serve as synthetic intermediates for various prostaglandins, are efficiently produced in a higher optical yield than the easily available racemic forms. be able to.

Effects of the Invention The feature of the method of the present invention is that it utilizes the optical activity of amylose and the asymmetric discrimination ability of rubamate derivatives to separate 4-hydroxy-2-cyclobentenones into R and S forms by, for example, liquid chromatography. It separates a substance into its optical isomers. It is superior to conventional manufacturing methods in the following points. ■Easy to operate (minutes M by liquid chromatography).

(2) In the case of a racemate, each optical isomer can be obtained at a yield close to 50% of the theoretical yield. (2) Optically resolved 4-hydroxy-2-cyclobentenones can directly serve as intermediates for various prostaglandins.

In addition, since it has a much higher asymmetric discrimination ability than optical resolution methods using polysaccharide derivatives such as cellulose, separation processing capacity is dramatically improved and manufacturing costs can be significantly reduced.

Example Hereinafter, the present invention will be explained in more detail with reference to Examples.

Example 1 Amylose tris(S)-1-phenylethyl rubbermate was treated with 3-adonoprobyltrimethoxysilane to produce large-pore silica gel (particle size 7 to lOμ, pore size 1000
~4000 people) &. : A 25 wt % loaded and techiral stationary phase was prepared, and this was prepared with a length of 25 cm and an inner diameter of 0.46 cm.
m column was packed. Hexane/2-probanol (
98/2) as the eluent and 4-t-butyldimethylsilyloxy-2-cyclobentenone (racemic form) at 25°C.
It was passed through the force ram at a flow rate of 0.5 ml/min. JASCO TRIROTARn was used as the chromatograph, and JASCO UV-100 - was used as the detector.
Optical resolution was performed using JASCO DIP-181C (wavelength 365 nm) for optical rotation detection. The obtained elution pattern is shown in FIG. As is clear from FIG. 1, it can be seen that by the optical resolution of the present invention, the (+) isomer elutes first, followed by the (-) isomer. The (-) body eluted later was [α]8”-6
7.0'' (C=1.0, methanol) and is the S form.The (-) form eluted later is [α]31+67.
0° (C=1.0, methanol) and is in the R form.

Example 2 4-t-butyldiphenylsilyloxy-2cyclopentenone (racemic form) was optically resolved in the same manner as in Example 1. However, the eluent composition was hexane/2-probanol (
9/1) was used. The elution pattern obtained is shown in FIG. As is clear from FIG. 2, by the optical resolution of the present invention, the (+) form elutes first (S form), followed by the (-) form (R form).

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 clear from FIG. 3, by the optical resolution of the present invention, the (+) form elutes first (S form), followed by the {-} form (R form).

Example 4 4-acetyloxy-2-cyclobentenone (racemic form) was optically resolved in the same manner as in Example 2. The obtained elution pattern is shown in FIG. As is clear from Figure 4,
Due to the optical resolution of the present invention, the (+) isomer is eluted first (R isomer)
, it can be seen that the (-) form is subsequently eluted (S form).

[Brief explanation of drawings]

Each figure shows the elution pattern of 4-hydroxy-2-cyclobentenones (racemic form) when amylose tris(S)-1-phenylethyl rubbermate was used. -Butyldimethylsilyloxy-2-cyclobentenone (Example 1). Figure 2 shows the elution pattern of 4-t-butyldiphenylsilyloxy-2-
The elution pattern of cyclobentenone (Example 2) is shown. FIG. 3 shows the elution pattern of 4-methyldiphenylsilyloxy-2-cyclobentenone (Example 3). Figure 4 shows 4-acetyloxy-2-cyclopentenone
The elution pattern of Example 4) is shown. In these figures, the horizontal axis represents time. In addition, the upper row of the chromatodaram in each figure is the JASCO DI.
It represents the optical rotation measured at a wavelength of 365 nm using a P-18IC polarimeter, and the area above the baseline indicates the (+) optical rotation, and the area below the baseline indicates the {-} optical rotation. The bottom row is JASCO U
Wavelength 230n using V-100-11IUV detector
UV absorption measured in m. Furthermore, peaks detected only by the UV detector and not detected by the optical polarimeter represent optically inactive impurities such as silanol derivatives.

Claims (1)

[Claims] 1. The following formula [I] ▲ Numerical formulas, chemical formulas, tables, etc. are included ▼...[I] [In the formula, R represents a hydroxyl protecting group. ] The following formula [II] is characterized by the optical resolution of 4-hydroxy-2-cyclopentenones represented by using an optically active carbamate derivative of amylose. ▲There are mathematical formulas, chemical formulas, tables, etc.▼... [II] [wherein R is the same as defined above. * represents an asymmetric carbon atom in which optical activity is induced. ] A method for producing optically active 4-hydroxy-2-cyclopentenones represented by: 2. In the above formulas [I] and [II], the protecting group for R is -SiR_1R_2R_3 (here, R_1, R_2, R
_3 is the same or different and is a C_1 to C_6 hydrocarbon group), a group that forms an acetal bond with the oxygen atom of a hydroxyl group, or an acyl group, the optically active 4-hydroxy-2 - A method for producing cyclopentenones. 3. Production of optically active 4-hydroxy-2-cyclopentenones according to claim 1 or 2, wherein the optically active carbamate derivative of amylose is amylose tris (S)-1-phenylethyl carbamate. Law.