JP2541197B2 - Optically active cyclopentene derivative and its production method - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention has the general formula [I] (Wherein A represents H, R'CO (R 'represents a lower alkyl group) and R represents a lower alkyl group) (hereinafter referred to as compound [I]). It is about.

The compound [I] is easily used as a synthetic intermediate for prostaglandins as shown in FIG. 1 and is (1S, 5R) -cis-2-oxabicyclo [3.3.0] oct-6-ene-3.
The compound can be converted to a -one [III] (hereinafter referred to as compound [III]).

[Prior Art] The following four methods are known so far as methods for producing the compound [III].

(1) Tetrahedron Letters311 (1970) (EJCorey,
R. Noyori), using the method described in
This is JOC, Vol.39 256 (1974) (EJCorey, Barry
B. Snider) to obtain compound [III] by optical resolution according to the method described.

(2) The method described in JP-A-50-151862.

That is, a racemic body was synthesized by utilizing the ortho-Claisen rearrangement of cis-3,5-dihydroxy-1-cyclopentene, and this was synthesized by JOC, Vo1.39 256 (1974) (E.
J. Corey, Barry B. Snider) to obtain compound [III] optically resolved by the method described in J. Corey, Barry B. Snider.

(3) JCSChem.Comm., 189 (1976) (Takano, Tanikawa,
Ogasawara) method.

That is, an ortho-Claisen rearrangement is carried out on an optically active (3R, 5S) -cis-5-acetoxy-3-hydroxycyclopentene [IV] obtained by asymmetric hydrolyzation by a microorganism to obtain [V]. A method for obtaining [III].

(4) JACS, 95 7171 (1793) (John J. Patridge,
Naresh K. Chadha).

That is, a method of synthesizing the compound [III] by utilizing asymmetric hydroboration.

[Problems to be Solved by the Invention] In the above methods (1) and (2), optical resolution of the racemate is required, so an expensive optical resolving agent is required and the resolving operation is complicated. There is a problem in that the resolution efficiency of the compound is poor and unnecessary enantiomers are wasted.

The method (4) requires an unstable raw material such as a borane compound and is not satisfactory as a practical manufacturing method.

Although the method (3) is superior to the above three methods, the starting material (3R, 5S) -cis-5-acetoxy-
It is difficult to efficiently obtain 3-hydroxycyclopentene [IV] with high optical purity, and the ortho-Claisen rearrangement for obtaining [V] requires a long reaction condition of 140 ° C. for 24 hours. In addition, a diacetoxy compound is produced from the raw material [IV] by a side reaction during the reaction.
When this diacetoxy compound is hydrolyzed, a meso-type diol compound is obtained. Since this compound has lost optical activity, it cannot be used for producing the target compound, unlike the present invention. Has the problem.

[Means for solving problems]

This time, the present inventors On the other hand, a method for producing compound [I], which is characterized by carrying out ortho-Claisen rearrangement, was found, and the present invention was completed.

This production method uses an optically active trans-1,4-cyclopentenediol derivative [II], which has not been noticed in the past, as a starting material and does not require a complicated optical resolution operation.
In addition, the method is superior to the method (3) in the following three points. That is, the compound [II] as a starting material can be easily obtained.

That is, asymmetric optical hydrolysis by the enzyme developed by the present inventors (Japanese Patent Application No. 61-76288) results in high optical purity (3S, 5R)-
5-acyloxy-3-hydroxycyclopentene [I
V] can be easily obtained, and this can be easily induced to the compound [II] by the Mitsunobu method.

The reaction conditions are mild.

By using the trans isomer, the reaction temperature and reaction time when synthesizing the compound [I] from the compound [II] became mild.

(In the formula, A means H, R ₁ CO (R ₁ is a lower alkyl group),
R means a lower alkyl group. ) A diacetoxy compound is produced from the compound [II] by a side reaction. When this diacetoxy compound is hydrolyzed, a trans diol compound is obtained. This product can be used for the production of the target compound as is clear from Example 3.

 Hereinafter, the present invention will be described in detail.

The compound [II] is heated together with an excess orthoacetic acid lower alkyl ester, if necessary, in the presence of an acidic catalyst at 110 to 170 ° C., preferably 120 to 140 ° C. for about 6 to 10 hours to perform so-called ortho-Claisen rearrangement. Compound [I] is produced. This reaction condition is much milder than the conventional method (3) of heating at 140 ° C. for 24 hours.

Acid catalysts used include phenol, o, m or p
-Nitrophenol, o, m or p-cresol, 2,4,
2,5,3,4,3,5 or 2,6-dimethylphenol, 2,6-
Phenols exemplified by di-t-butylphenol, 2,4,6-tri-sec-butylphenol, 2,4,6-tri-t-butylphenol, hydroquinone, α, β-naphthol, acetic acid, propionic acid, Lower fatty acids exemplified by butyric acid, isobutyric acid, cyclohexanecarboxylic acid, valeric acid, malonic acid, succinic acid, pivalic acid, etc., benzoic acid, aromatic carboxylic acids exemplified by m-chlorobenzoic acid, benzenesulfonic acid , Sulfonic acids exemplified by paratoluenesulfonic acid, etc.
Mineral acids exemplified by hydrochloric acid, sulfuric acid, etc., and Lewis acids exemplified by aluminum chloride, zinc chloride, iron chloride, boron trifluoride, etc., are preferably phenols and carbon numbers in order to proceed the reaction efficiently. 2-6 fatty acids and aromatic carboxylic acids are used.

The catalyst amount is used in the range of 0.001 to 50 mol% with respect to the raw material, and preferably in the range of 5 to 30 mol%.

The reaction solvent is not necessarily required, but a solvent such as n-octane, toluene, o, m or p-xylene, di-n-butyl ether, etc. that does not participate in the reaction is used. The orthoacetic acid lower alkyl ester may be used in a large excess as a solvent for the compound [II] to carry out the reaction.

By stirring the obtained compound [I] (when A = R ₁ CO (where R ₁ is a lower alkyl group)) in a lower alcohol such as methanol in the presence of an alkali carbonate for a long time (3R, 4
R) -trans-4-hydroxy-3-alkoxycarbonylmethylcyclopentene is produced.

In the following, a high yield is induced to the bicyclic lactone [III] according to a known method (see FIG. 1).

As described above, the compound [I
By using the milder ortho-Claisen rearrangement reaction with [I] as the starting material, it became possible to practically produce the important synthetic intermediate [III] of prostaglandins, which are important as pharmaceuticals.

[Examples and reference examples]

Hereinafter, the present invention will be specifically described with reference to Examples and Reference Examples. The present invention is not limited to these examples.

Example 1 Synthesis of (3R, 4R) -trans-4-acetoxy-3-ethoxycarbonylmethylcyclopentene (I: A = Ac, R = Et) (3R, 5R) -trans-5-acetoxy-3-hydroxycyclopentene (II: A = Ac) 207 mg (1.46 mmol),
Pivalic acid 30 mg (0.29 mmol) and ethyl orthoacetate 7 ml
(38.2 mmol) was heated at 120 ° C. for 8 hours under a nitrogen stream. During this time, after 3 hours and 4 hours, 20 mg (0.20 mmol) of pivalic acid
Added one by one. After evaporating the solvent, the residue was separated and purified by silica gel column chromatography (20 g, hexane: ether = 4: 1 (v / v), and (3R, 4R) -trans-4-acetoxy-3-ethoxycarbonylmethylcyclopentene (I : A = Ac, R = Et) was obtained (157 mg, 51% yield) ¹ H-NMR (60 MHz, CDCl ₃ ) δppm: 1.07 (3H, t, J = 7Hz), 2.00 (3H, s), 2.2 to 3.3 (5H, m), 4.1 (2H, q, J = 7Hz), 5.03 (1H, dq, J = 5Hz, J = 3Hz), 5.63 (2H, br s) MS; m / e = 167 (4%, [M-OEt] ⁺ ), 152 (100%, [M-AcOH] ⁺ ) ▲ [α] ²⁵ _D ▼ = 110.2 (c = 0.893, CHCl ₃ ) Example 2 (3R, 4R)- Synthesis of trans-4-hydroxy-3-ethoxycarbonylmethylcyclopentene (I; A = H, R = Et) (3R, 4R) -trans-4-acetoxy-3-ethoxycarbonylmethylcyclocyclopentene (I: A = Ac , R ＝ E
t) 210 mg (0.99 mmol) is dissolved in 10 ml of dry ethanol,
To this, 960 mg (6.96 mmol) of potassium carbonate was added, and the mixture was stirred at room temperature for 5 hours. After adding 50 ml of ether and filtering, the solvent was distilled off. The obtained residue was separated and purified by silica gel column chromatography (5 g, hexane: ether = 3: 1 (v / v)) to give (3R, 4R) -trans-4-hydroxy-3-ethoxycarbonylmethylcyclopentene (I : A = H, R = Et) (145 mg, yield 86%) was obtained. ¹ H-NMR (60 MHz, CDCl ₃ ) δppm: 1.25 (3H, t, J = 7Hz), 1.9 to 3.2 (6H, m), 4.13 (3H, m), 5.3 to 5.8 (2H, m) MS; m / e = 170 (1%, M ⁺ ), 152 (7% [M-H ₂ O] ⁺ ), 79 (100%, Rh ⁺ ) ▲ [α] ²⁵ _D ▼ = -55.4 ° (c = 1.017, CHCl ₃ ) Reference Example 1 Derivation to (1S, 5R) -cis-2-oxabicyclo [3.3.0] oct-6-en-3-one [III] (3R, 4R) -trans- in 1 ml of pyridine. 4-hydroxy-3-ethoxycarbonylmethylcyclopentene (I;
To a solution of 150 mg of A = H, R = Et) was added 46 mg of methanesulfonyl chloride at 0 ° C., the mixture was stirred at 0 ° C. for 1 hour, and poured onto crushed ice. This mixture was washed with 15 ml of saturated saline and extracted 3 times with 15 ml of diethyl ether. Ether layer is 10% sulfuric acid
10 ml, saturated sodium carbonate aqueous solution 10 ml and saturated saline solution 10
Washed with ml. It was dried over magnesium sulfate and the solvent was distilled off at room temperature. Obtained oily substance, tetrahydrofuran 6 ml
And 2 ml of water at 0 ° C. in a solution of 2N sodium hydroxide 4
ml was added dropwise. The mixture was vigorously stirred at 0 ° C for 1 hour and at room temperature for 18 hours. This solution was diluted with 10 ml of water and diluted with diethyl ether 10
Extracted 3 times with ml. The ether layer was extracted with 10 ml of water. The aqueous layers were combined, cooled to 0 ° C. and acidified with excess 6N aqueous sulfuric acid. The acidic solution was saturated with sodium chloride and extracted 3 times with 20 ml of methylene chloride. The methylene chloride layers were combined, washed with a saturated aqueous solution of sodium hydrogen carbonate, and dried over magnesium sulfate. After distilling off the solvent, silica gel column chromatography (10 g, hexane: ether = 3: 1 (v /
(1S, 5R) -cis-2-oxabicyclo [3.3.0] oct-6-en-3-one [III] after purification in v))
87 mg (yield 80%) was obtained. ¹ H-NMR (60 MHz, CDCl ₃ ) δppm: 2.0 to 3.0 (4H, m), 3.45 (1H, m), 5.05 (1H, m), 5.63 (2H, m) ▲ [α] ²⁰ _D ▼ =- 100.8 ° (c = 1.1, MeOH) Example 3 Ortho-Claisen rearrangement for (3R, 5R) -trans-3,5-cyclopentenediol (II: A = H) (3R, 5R) -trans-3,5- Cyclopentenediol (II: A = H) 500 mg (5.0 mmol), hydroquinone 100 mg
(0.9 mmol) and 5 ml (27.3 mmol) of ethyl orthoacetate were heated under a nitrogen stream at 130 ° C. for 6 hours. The oily substance obtained by distilling off the solvent was subjected to silica gel column chromatography (50
g, hexane: ether = 3: 1 (v / v)) and (3R, 4R) -trans-4-acetoxy-3-ethoxycarbonylmethylcyclopentene (I: A = Ac, R = Et)
30 mg (yield 10%), (3R, 4R) -trans-4-hydroxy-3-ethoxycarbonylmethylcyclopentene (I: A = H, R = Et) 240 mg (yield 28%) and (3R, 5R ) −
150 mg (yield 21%) of trans-5-acetoxy-3-hydroxycyclopentene (II: A = Ac) was obtained.

 ─────────────────────────────────────────────────── --Continued Front Page (56) References US Patent 3933892 (US, A) J. Am. C. S. CHEM. COMM. 1976, p. 189-190

Claims (1)

(57) [Claims] 1. A general formula [II] [In the formula, A means H or R'CO (R 'is a lower alkyl group). )] Is heated to 120 to 140 ° C. in the presence of an orthoacetic acid lower alkyl ester and a compound of the general formula (II) in the presence of 5 to 30 mol% of an acid catalyst. I] [In the formula, A means H or R'CO (R 'is a lower alkyl group), and R means H or a lower alkyl group. ] The manufacturing method of the compound represented by these.