JPH06321831A - Production of 1-substituted 1,4-dihydroxy-2-cyclopentenone derivative - Google Patents

Abstract

PURPOSE:To provide a new industrial producing method simplified in operation, excellent in yield and purity of the subject compound being a synthetic intermediate for 4-hydroxy-2-cyclopentenone compounds having antiulcer activity or therepeutic activity against osteoporosis. CONSTITUTION:R body or S body of 4-hydroxy-2-cyclopentenone of formula I or a mixture containing both in arbitrary ratio reacts with a compound of the formula RLi (R is substituted or unsubstituted 1-10C alkyl, alkenyl or alkynyl) of 1-5 equivalent, preferably 2 equivalent based on the compound to provide the objective 1-substituted 1,4-dihydroxy-2-cyclopentenone derivative of formula II (relative position of OH on five-member ring is cis) or the compound of formula I is treated with an organolithium compound of the formula R<1>Li (R<1> is 1-10C hydrocarbon group) substantially equivalent to the compound of I to produce a lithium salt of formula III and the resultant lithium salt reacts with a compound of the formula RLi to provide the objective compound of formula II.

Description

Detailed Description of the Invention

[0001]

The present invention relates to 4-hydroxy-2, which has an excellent anti-cancer activity or an excellent osteoporosis therapeutic activity.
-Yield of optically active cyclopentenediols, which is an intermediate necessary for producing a cyclopentenone compound,
The present invention relates to a novel industrial production method which is excellent in terms of purity and the like and is easy to operate.

[0002]

BACKGROUND OF THE INVENTION The present inventors have disclosed in JP-A-62-96438 that 4-hydroxy-2-cyclopentenones have anticancer activity. In addition, JP-A-1-13
In No. 036, it was revealed that these compounds have a bone formation promoting action. The present inventors have also published European Publication No. 338796 and International Publication No. WO91 / 0576.
No. 6 discloses that 2-substituted-4-hydroxy-2-cyclopentenones have an osteogenesis promoting action.

[0003]

DISCLOSURE OF THE INVENTION The present inventors have found that optically active 4-substituted-4-hydroxy-2-cyclopentenones (1) or optically active 2-substituted-4-substituted-4-hydroxy-2-hydroxy-2. -As a result of earnest research on a simple and industrial synthetic method of optically active cyclopentenediol, which is necessary for synthesizing cyclopentenones (2), a novel synthetic method shown in the present invention has been reached. Is.

[0004]

[Chemical 4]

That is, according to the conventional synthesis method, for example, 1,2-to 4-hydroxy-2-cyclopentenone is protected as shown in Reference Example 1 or the following route [1].
-Since there was no stereoselectivity in the addition reaction, a precise separation step was required to obtain 4-substituted-4-hydroxy-2-cyclopentenones having high optical purity. Therefore, the conventional method has not been an industrially useful route.

[0006]

[Chemical 5]

The inventors of the present invention have conducted earnest research to solve the above problems, and as a result, formed a lithium salt in advance without protecting the hydroxyl group of 4-hydroxy-2-cyclopentenone as a starting material. As a result of the subsequent 1,2-addition reaction, it was surprisingly found that the selectivity of the 1,2-addition reaction was surprisingly improved, and the present invention was achieved.

[0008]

DETAILED DESCRIPTION OF THE INVENTION The following formula [III] obtained in the present invention:

[0009]

[Chemical 6]

(In the formula, R represents a substituted or unsubstituted alkyl group, alkenyl group, or alkynyl group having 1 to 10 carbon atoms. The relative position of the hydroxyl group on the 5-membered ring is cis.)
1-substituted 1,4-dihydroxy-2-cyclopentene represented by the following formula [I]

[0011]

[Chemical 7]

The R-form or S-form of the compound represented by the formula or a mixture of them in any proportion is represented by the following formula [II] RLi ... [II] (wherein R is a substituted or unsubstituted C 1-10 carbon atom). Or an alkyl group, an alkenyl group, or an alkynyl group).
Alternatively, the cyclopentenone compound represented by the above formula [I] is substantially equivalent to the following formula [IV] R ¹ Li ... [IV] (In the formula, R ¹ represents a hydrocarbon group having 1 to 10 carbon atoms. )
Treated with an organolithium compound represented by the following formula [V]

[0013]

[Chemical 8]

It can be produced by producing a lithium salt represented by and reacting this with an organolithium compound represented by the above formula [II].

Preferred examples and explanations of various definitions in the present invention will be explained in detail below.

In the above formula [II] or [III], R
Represents an alkyl group having 1 to 10 carbon atoms, an alkenyl group or an alkynyl group. These may be linear or branched.

Examples of the unsubstituted alkyl group include methyl, ethyl, n-propyl, iso-propyl and n-
Butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n
—Nonyl group, n-decyl group and the like can be mentioned.

Examples of the unsubstituted alkenyl group include:
Ethenyl, 1-propen-1-yl, 2-propen-1
-Yl, 1-butene-1-yl, 1,3-butadiene-
1-yl, 2-butene-1-yl, 1-pentene-1-
2-penten-1-yl, 1-hexen-1-yl, 2-hexen-1-yl, 1,5-hexadiene-
1-yl, 3-hexene-1-yl, 1-heptene-1
Examples thereof include groups such as -yl, 1-octen-1-yl, 1,7-octadien-1-yl, 1-nonen-1-yl group and 1-decen-1-yl group.

Examples of the unsubstituted alkynyl group include:
Ethynyl, 1-propyn-1-yl, 2-propyne-1
-Yl, 1-butyn-1-yl, 3-butene-1-in-1-yl, 2-butyn-1-yl, 1-pentyl-1
-Yl, 2-pentyn-1-yl, 1-hexyne-1-
Ile, 2-hexyne-1-yl, 5-hexene-1-in-1-yl, 3-hexyne-1-yl, 1-heptin-1-yl, 1-octin-1-yl, 7-octyne-
Examples thereof include 1-in-1-yl, 7-octen-1-in-1-yl, 1-nonin-1-yl group and 1-decyn-1-yl group.

These alkyl group, alkenyl group and alkynyl group may have a substituent. Examples of this substituent include —OR ² (wherein R ² is substituted with a halogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, a phenyl group which may be substituted with an alkoxy group having 1 to 4 carbon atoms, or the like). C1 to C6 alkyl group which may be contained; halogen atom, C1 to C4 alkyl group or C1 to C4
A phenyl group which may be substituted with an alkoxy group; a halogen atom, an alkyl group having 1 to 4 carbon atoms or 1 to 4 carbon atoms
3 to 8 carbon atoms which may be substituted with an alkoxy group of 4
Represents a cycloalkyl group. ) Is mentioned.

Examples of --OR ² are; as the alkoxy group having 1 to 6 carbon atoms, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, n-pentoxy, or n-hexoxy group; or a phenoxy group. And so on. Typical examples of the alkoxy group having 1 to 6 carbon atoms which is substituted with a halogen atom in —OR ² include a chloromethoxy group, a dichloromethoxy group and a trifluoromethoxy group. -OR
^{When 2} is a phenoxy group, there may be a substituent on the benzene ring, and as the substituent, a halogen atom such as chlorine, bromine, or fluorine; a methyl, ethyl, propyl, or butyl group having 1 to 4 carbon atoms. Alkyl group; or methoxy,
1 to 1 carbon atoms such as ethoxy, propoxy or butoxy groups
4 alkoxy group and the like.

The various aliphatic hydrocarbon groups described above may be further substituted with a phenyl group or a cycloalkyl group having 3 to 8 carbon atoms. In this case, the phenyl group or 3 carbon atoms is substituted.
As described above, examples of the substituent of the cycloalkyl group having 8 to 8 include a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, and the like.

R ¹ in the above formula [IV] represents an unsubstituted or substituted hydrocarbon group having 1 to 10 carbon atoms. When the hydrocarbon group is an alkyl group, it may be linear or branched. It is preferably unsubstituted, for example,
Methyl, ethyl, n-propyl, iso-propyl, n
-Butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl,
Examples thereof include n-nonyl group and n-decyl group. Particularly preferred are readily available methyl, n-butyl, t
-Butyl is mentioned. In this case, any organolithium compound other than lithium hydrocarbon represented by the above formula [IV] can be used as long as it basically produces the above formula [V] from the above formula [I]. Good.

Next, the method for producing the optically active 1-substituted 1,4-dihydroxy-2-cyclopentenone derivative represented by the above formula [III] of the present invention will be described in detail below.

[Step A] The compound [III] has the above formula [I].
It can be synthesized by reacting 4-hydroxy-2-cyclopentenone represented by the formula with a lithium compound [II]. The lithium compound [II] is usually the compound [I]
It is sufficient to use 1 equivalent or more to about 5 equivalents, but it is basically preferable to use 2 equivalents. The reaction is usually carried out in an organic solvent, for example, diethyl ether, n-hexane, tetrahydrofuran, etc. or a mixture thereof is used, but any solvent other than these solvents may be used as long as it does not adversely affect the reaction. . The reaction time and reaction temperature are not particularly limited, but usually the reaction is completed within 10 minutes to 1 day under room temperature and cooling. It is preferably carried out in an inert gas atmosphere at a temperature range of -10 ° C to -100 ° C.

[Step B] The compound [III] has the above formula [I].
4-hydroxy-2-cyclopentenone represented by
It can be synthesized by treating with an equivalent amount of the organolithium compound and then reacting with the lithium compound [II]. The lithium compound [II] may be usually used in an amount of about 0.5 to 5 equivalents to the compound [I], but it is basically preferable to use 1 equivalent. The reaction is usually carried out in an organic solvent, for example, diethyl ether, n-hexane, tetrahydrofuran, etc. or a mixture thereof is used, but any solvent other than these solvents may be used as long as it does not adversely affect the reaction. . The reaction time and reaction temperature are not particularly limited, but usually 10 minutes to 1 at room temperature and under cooling.
The reaction ends during the day. It is preferably carried out in an inert gas atmosphere at a temperature range of -10 ° C to -100 ° C.

The optically active compound [III] thus obtained
Is a compound useful as an intermediate necessary for producing a 4-hydroxy-2-cyclopentenone compound having excellent anticancer activity or excellent osteoporosis therapeutic activity.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto.

[0029]

Example 1 (1S, 4R) -1- (4-phenoxybutyl) -1,
Synthesis of 4-dihydroxy-2-cyclopentenone

[0030]

[Chemical 9]

T-BuLi (1.54M pentane solution)
Phenoxybutyl bromide (2.35 g, 10 mmo) obtained by cooling (10 ml, 15.4 mmol) to -78 ° C.
Phenoxybutyllithium was prepared by adding dropwise to a dry diethyl ether solution (20 ml) of 1) in a nitrogen stream for 10 minutes and further stirring for 2 hours.

On the other hand, a different container was prepared (4R) -4-
Hydroxy-2-cyclopentenone (626 mg, 6.
4 mmol) in dry tetrahydrofuran (10 ml) at −78 ° C. under a nitrogen stream, n-butyllithium (1.68 M hexane solution) (3.8 ml, 6.4 mm).
ol) was added dropwise over about 10 minutes. The phenoxybutyllithium prepared above was added all at once to the reaction mixture which was stirred for 30 minutes as it was. The reaction mixture was further stirred for 1 hour, and then the reaction was terminated with a saturated aqueous solution of ammonium chloride. The reaction mixture was extracted twice with ethyl acetate, and the obtained organic layer was dried over anhydrous magnesium sulfate. The organic solvent was distilled off under reduced pressure to obtain a crude product. This is subjected to silica gel column chromatography (hexane: ethyl acetate =
1: 1 to ethyl acetate), (1S, 4R) -1-
(4-phenoxybutyl) -1,4-dihydroxy-2
-Cyclopentene (1.19g, 75%, cis / tr
ans = 99: 1 HPLC analysis: column-YMC-p
ack ODS-AM, solvent-acetonitrile / water = 7
0/30, 0.05% trifluoroacetic acid, flow rate 2.5m
l / min. Retention time cis; 12.5 minutes, tran
s; 8.0 min) was obtained.

¹ H-NMR (90 MHz, CDCl ₃ ,
δppm): 1.40 to 1.85 (8H, m), 1.9
0-2.20 (1H, brs, -OH), 2.43 (1
H, dd, J = 7.0, 14.0 OHz), 3.96
(2H, t, 6.3 Hz), 4.70 to 4.71 (1
H, m), 5.90-5.99 (2H, m), 6.87
Up to 6.96 (3H, m), 7.20 to 7.30 (2H,
m).

[0034]

Example 2 (1R, 4S) -1- (4-phenoxybutyl) -1,
Synthesis of 4-dihydroxy-2-cyclopentenone

[0035]

[Chemical 10]

T-BuLi (1.54M pentane solution)
Phenoxybutyl bromide (2.35 g, 10 mmo) obtained by cooling (10 ml, 15.4 mmol) to -78 ° C.
Phenoxybutyllithium was prepared by adding dropwise to a dry diethyl ether solution (20 ml) of 1) in a nitrogen stream for 10 minutes and further stirring for 2 hours.

The prepared phenoxybutyllithium was cooled to −78 ° C. in a nitrogen stream and (4S) -4-hydroxy-2-cyclopentenone (313 mg, 3.2 mmo).
To a solution of 1) in dry tetrahydrofuran (10 ml) was added dropwise over about 25 minutes. The mixture was stirred for 1 hour as it was, and the reaction was terminated with a saturated aqueous solution of ammonium chloride. The reaction mixture was extracted twice with ethyl acetate, and the obtained organic layer was dried over anhydrous magnesium sulfate. The organic solvent was distilled off under reduced pressure to obtain a crude product. This was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1 to ethyl acetate) to give 1- (4-phenoxybutyl) -1,4.
-Dihydroxy-2-cyclopentene (674 mg, 8
5.0%, cis / trans = 99: 1 HPLC analysis conditions-see Example 1).

¹ H-NMR (90 MHz, CDCl ₃ ,
δppm): 1.40 to 1.85 (8H, m), 1.9
0-2.20 (1H, brs, -OH), 2.43 (1
H, dd, J = 7.0, 14.0 OHz), 3.96
(2H, t, 6.3 Hz), 4.70 to 4.71 (1
H, m), 5.90-5.99 (2H, m), 6.87
Up to 6.96 (3H, m), 7.20 to 7.30 (2H,
m).

[0039]

[Reference example 1]

[0040]

[Chemical 11]

The 5-liter three-necked flask was replaced with nitrogen,
1.57M t-butyllithium pentane solution 1.25
L was added and cooled to -70 ° C. 1-Bromo-4-
A 1.25 liter ether solution of 300 g phenoxybutane was added. After stirring at -70 ° C for 1 hour (4S)
A solution of 164 g of -4-t-butyldimethylsilyloxy-2-cyclopentenone in 500 ml of tetrahydrofuran was added, and the mixture was stirred for 1 hour. Aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. After filtration and concentration, it was subjected to silica gel column chromatography to obtain (1R, 4S) -1-
Hydroxy-4-t-butyldimethylsilyloxy-1
-(4-phenoxybutyl) -2-cyclopentene and (1S, 4S) -1-hydroxy-4-t-butyldimethylsilyloxy-1- (4-phenoxybutyl) -2
252 g (90% yield) of a 88:12 mixture of cyclopentenone was obtained.

¹ H-NMR (CDCl ₃ , δppm):
0.07 (6H, s), 0.89 (9H, s), 1.4
~ 1.9 (7H, m), 2.22 (1H, dd, J = 1
3.9, 6.6 Hz), 3.97 (2H, t, J = 6.
3 Hz), 4.8 to 4.9 (1 H, m), 5.75 to
5.9 (2H, m), 6.8 to 7.0 (3H, m),
7.2-7.35 (2H, m). HPLC analysis conditions: column-Zorbax sil, solvent-2% isopropyl alcohol / n-hexane, flow rate-0.7 ml / min, retention time-cis; 9.0 minutes,
trans 12.3 minutes.

[0043]

According to the production method of the present invention, a high stereoselectivity of 1,2 addition reaction to 4-hydroxy-2-cyclopentenone is obtained, and an optically active 1-substituted 1,4-dihydroxy compound is obtained. A 2-cyclopentenone derivative can be obtained with high selectivity.

Claims (3)

[Claims] 1. The following formula [I]: The following formula [II] RLi ... [II] (wherein R represents a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, A compound represented by an alkenyl group or an alkynyl group) is reacted to obtain a compound represented by the following formula [III] (In the formula, R has the same definition as above, and the relative position of the hydroxyl group on the 5-membered ring is cis.)
Process for producing 4-dihydroxy-2-cyclopentenone derivative 2. A cyclopentenone compound represented by the above formula [I] in the R-form, S-form or a mixture thereof at any ratio is substantially equivalent to the following formula [IV] R ¹ Li ... [IV] ( In the formula, R ¹ represents a hydrocarbon group having 1 to 10 carbon atoms.)
Treated with an organolithium compound represented by the following formula [V] 1-substituted 1,4 represented by the above formula [III], which is characterized in that a lithium salt represented by the formula [3] is formed, and this is reacted with the organolithium compound represented by the above formula [II]. -A method for producing a dihydroxy-2-cyclopentenone derivative. 3. The method for producing a 1-substituted 1,4-dihydroxy-2-cyclopentenone derivative according to claim 1 or 2, wherein R in the above formula is a methyl, butyl or phenoxybutyl group.