JPS5822020B2 - Cyclopentanone carbon ester - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for preparing novel cyclopentanone carboxylic acid ester derivatives having the general formula.

In the above general formula, R1 is a hydrogen atom or, for example, methyl,
Represents a lower alkyl group such as ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl-n-pentyl, isopentyl, and R2 is a hydrogen atom;
For example, methyl, ethyl, n-propyl, isopropyl,
Lower alkyl groups such as n-butyl, isobutyl, tertjfyl, n-pentyl, isopebutyl or such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, impropoxycarbonyl, n-
butoxycarbonyl, imbutoxycarbonyl, ter
Represents a lower alkoxycarbonyl group such as t-butoxycarbonyl, and R3 is, for example, methyl, ethyl, n-fluorite, isopropyl, n-butyl, isobutyl, tert
R4 represents a lower alkyl group such as -butyl, and R4 represents a lower alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, or tert-butyl.

As a result of various research into the production of prostaglandins, the present inventors have discovered that novel cyclopentanone carboxylic acid ester derivatives represented by the above general formulas (I) and (II) are prostaglandin derivatives useful as pharmaceuticals. The present invention was completed by discovering that it can be used as a raw material for important synthetic intermediates.

Conventionally, methods for producing prostaglandi intermediates such as those represented by general formulas (IX) and (XV) described below include, for example, the method of Crabbe et al. (P, Crabbe', A, G
u-zma'n: Tctrahedron Le
tters, 1972, p. 115] or method 1 of Colley et al. J.

Crey + N., M., Weinshenker, T.;
5 chaaf.

W.Huber: The Journal of
The AmeI-i-can Chemical 5
ociety+ vol. 91, p. 5675 (1969)]
However, these methods have the disadvantage that thallium hydroxide, which is toxic, or 2-chloro-acrylonitrile, which is stimulant and toxic, must be used as a reagent.

The method for producing intermediates using the method of the present invention does not use these reagents as reagents, and moreover, the method for producing intermediates using the method of the present invention does not require the use of these reagents as reagents, and furthermore, the method for producing intermediates using the method of the present invention does not require the use of these reagents as reagents.
．． This provides an advantageous method when the objective is to obtain a novel compound having a substituent such as 11-dimethyl introduced therein.

According to the method of the present invention, the compound having the general formula (I) and/or (n) is formed by the general formula (wherein R1, R2 and R3 have the same meanings as defined above).

) is a compound having the general formula % formula % () (wherein R4 has the same meaning as described above, and R5 is n
-Represents a lower alkyl group such as butyl or an aryl group such as phenyl.

) and, if necessary, separation of the reaction products.

In carrying out the method of the present invention, the reaction is accomplished by contacting a compound having the general formula (1) with a compound having the general formula (2).

The reaction is carried out in the presence of a solvent, and the solvent used is not particularly limited to that used in ordinary Witschig reactions, such as methylene chloride, chloroform, ethylene dichloride, carbon tetrachloride, etc. Examples include inert organic solvents such as halogenated hydrocarbons, aromatic hydrocarbons such as benzene, toluene, and xylene, and ethers such as ethyl ether, dimethoxyethane, tetrahydrofuran, and dioxane.

Preferred (moss chloroform is used.

The reaction temperature is not particularly limited and is usually carried out at room temperature to the reflux temperature of the solvent, but it is preferably carried out at room temperature to around 60°C.

The reaction time varies depending on the type of raw material compound, reaction temperature, etc., but is approximately 5 hours to 5 days.

Usually, this reaction can be carried out preferably by using 3 to 3 moles of the Witzig reagent having the general formula (■) per 1 mole of the compound having the general formula (IID). .

After completion of the reaction, the target compound is recovered from the reaction mixture according to conventional methods.

For example, after the reaction is completed, the reaction mixture is washed with dilute hydrochloric acid to remove unreacted Witzig reagent, and the target compound is
Alkaline carbonate aqueous solution such as 0% potassium carbonate aqueous solution
If it is soluble, it is dissolved again, and the obtained aqueous alkali carbonate solution is washed with an organic solvent such as ether.The aqueous alkali solution layer is made acidic with an acid such as hydrochloric acid, and the alkali aqueous solution is dissolved again. The target compound can be obtained by extracting with an organic solvent such as and distilling off the solvent from the obtained extract; if the target compound is poorly soluble in an aqueous alkali carbonate solution, it can be extracted from the reaction mixture. The solvent was distilled off, the unreacted Witschig reagent precipitated by adding an organic solvent such as ether to the residue, and the organic solvent layer was washed with dilute hydrochloric acid and dilute potassium carbonate aqueous solution, and the resulting extract was By distilling off the solvent, the target compound can be obtained.

The obtained target compound exists as a mixture of isomers related to the double bond ρ, the above-mentioned general formula 〇) and (In), and its carbonyl group is in the enol type or keto type.

Normally, when these compounds are used as intermediates in the production of prostaglantin derivatives, it is not necessary to separate and purify the two since the same compound will be obtained even if they are used in the mixture in the next step. However, if further separation is required, it can be purified by conventional methods such as recrystallization and column chromatography.

The compounds having the general formulas (I) and (formula) obtained by the method of the present invention are compounds that can be used as raw materials for important intermediates in the production of prostaglandin derivatives, as exemplified below.

In the above formula, R1, R2, R3 and R4 have the same meanings as described above.

The first step is a step of producing a compound having the general formula (1), and is achieved by reducing the compound having the general formula (I) and (ml).

The reaction is carried out using a reducing agent in the presence of a solvent.

The reducing agent to be used is particularly one that converts only the double bond into an ethylene group without reducing the carbonyl group (although there is no limitation, catalysts such as palladium-carbon, platinum oxide, Raney nickel, etc.) are used. Catalytic reduction methods using hydrogen in the presence of hydrogen are preferred.

The second step is a step of producing a compound having the general formula (■), and is achieved by decarboxylating the compound having the general formula (■).

The reaction is carried out using a decarboxylating agent in the presence of a solvent.

The decarboxylating agent used is not particularly limited as long as it decarboxylates ordinary β-keto ester compounds, but examples include mineral acids such as hydrochloric acid and sulfuric acid, sodium chloride, sodium chloride, and sodium cyanide. Dimethyl sulfoxide, lithium iodide-collidine, and the like are preferred.

In this reaction, when a mineral acid such as hydrochloric acid is used as a decarboxylating agent and heated, a dicarboxylic acid is produced as a reaction product, so the resulting compound can be processed using the usual esterification method.
Therefore, the desired ester compound having the general formula (VD) can be obtained.

Esterifying agents used include, for example, diazoalkanes such as diazomethane, diazoethane, diazo-n-propane, diazoisopropane; methanol, ethanol, n-propanol, impropanol, n-butanol, imbutanol, tert- Alcohols that form ester groups such as butanol and hydrochloric acid, hydrobromic acid,
Preferably, mineral acids such as sulfuric acid or organic acids such as benzenesulfonic acid or p-toluenesulfonic acid are used.

The third step is a step of producing a compound having the general formula (4), in which the compound having the general formula (■) is reduced,
Lactonization is then accomplished.

The reducing agent used is a stereospecific t
Although there is no particular limitation as long as it reduces this, for example, metal hydride compounds such as potassium hydrogenation)-5ec-butylboron, lithium 5ec-butylborohydride, or Raney nickel are suitable. used.

Lactonization of the resulting reduction reaction product is then carried out by treating the reaction mixture with a mineral acid such as hydrochloric acid or sulfuric acid.

The fourth step is a step of producing a compound having the general formula (■), and is achieved by hydrolyzing the compound having the general formula (■).

The reaction is carried out using a hydrolysis reagent in the presence of a solvent.

The hydrolysis reagent used is not particularly limited as long as it can hydrolyze ordinary ester compounds, but mineral acids such as hydrochloric acid and sulfuric acid are preferred.

The fifth step is a step of producing a compound having the general formula (1) O, and is achieved by reducing the compound having the general formula (■).

The reaction is carried out using a reducing agent in the presence of a solvent.

The reducing agent to be used is not particularly limited as long as it converts only the carboxyl group into the alcohol without reducing the lactone ring. It is preferable to react the halogen carbonic ester with ethyl chlorocarbonate in the presence of a base to obtain a mixed acid anhydride, and to this reaction, a reducing agent such as sodium borohydride is added.

Using the compounds having the above general formulas (I) and (It) as starting materials, the intermediate compound for the synthesis of a brostane grandein derivative having a hydroxyl group at the 11-position is obtained through the steps exemplified below. be able to.

80 In the above formula,
R3 has the same meaning as defined above, R6 represents a lower alkyl group, and LAX represents a halogen atom such as chlorine or bromine.

The first step is a step of producing a compound having the general formula (XI), in which the substituent R1 is a hydrogen atom and R2 is a lower alkoxycarbonyl group. Partial hydrolysis of the compound having formula (X) is thus achieved.

The reaction is carried out using a hydrolyzing agent in the presence of a solvent.

The hydrolyzing agent is not particularly limited as long as it hydrolyzes only the 3α-position carboxylic ester without affecting other parts of the compound, but barium hydroxide, calcium hydroxide, etc. Alkaline earth metal hydroxides are preferred.

The second step is a step of producing a compound having the general formula (XD), and is achieved by bringing the compound having the general formula (XD) into contact with a halogenating agent.

The halogenating agent used is not particularly limited as long as it converts a normal carboxylic acid into an acid halide, but thionyl halides such as thionyl chloride and thionyl bromide, oxalic acid chloride, oxalic acid bromide, Oxalic acid halide is preferred.

The third step is a step of producing a compound having the general formula (■), and is achieved by bringing the compound having the general formula (X[I) into contact with a methylating agent.

The methylating agent used is not particularly limited as long as it converts a normal carboxylic acid halide into a methyl ketone compound, but examples include dimethyl copper lithium, methyl magnesium chloride di cadmium chloride, methyl magnesium promide-zinc chloride, etc. Methyl metal compounds are preferred.

The fourth step is a step of producing a compound having the general formula (xIvX), and is achieved by contacting the compound having the general formula (X[I[)] with a peracid.

The filtered acid used is the usual Bayer-Villiger (
Although there are no particular limitations as long as they can be used in this reaction, pertrifluoroacetic acid, peracetic acid, m-chloroperbenzoic acid, and the like are preferred.

The fifth step is a step of producing a compound having the above formula (XV), and is achieved by hydrolyzing the compound having the above general formula (■).

The reaction is carried out using a hydrolysis reagent in the presence of a solvent.

The hydrolysis reagent used is not particularly limited as long as it hydrolyzes ordinary ester compounds, but hydrochloric acid,
Mineral acids such as sulfuric acid are preferred.

In each of the above steps, each target compound can be obtained by treating the reaction mixture in a conventional manner after the reaction is completed.

The obtained target compound can be further purified, if necessary, using conventional methods such as column chromatography, thin layer chromatography, etc.

The compound having the general formula (IX) or formula (XV) thus obtained is used as an intermediate, for example, by the method of Crabbe et al. (P, Crabbe', A, Guzm
a'n :Tetrahedron Letters
s 1972, p. 115], the method of Colli et al.
, J., Corey, N., M.

Weinshenker y T., 5chaaf
yW-Huber 2The Journal
of The American Chemi-c
al 5ociety, volume 91, page 5675 (196
9)] or the method of Pibby et al. (R-PeeltJ
, 5utherland: Ochemical
Community 1974, 1
Page 51] Thus, it is possible to produce natural prostaglandin derivatives as well as novel synthetic prostaglandin derivatives that are useful as pharmaceuticals.

The method of the present invention will now be explained in more detail with reference to Examples and Reference Examples.

Example ■ 2.2-dimethyl-4-carboethoxymethylene-5-
Oxo-cyclopencune-1,3-dicarboxylic acid dimethyl ester and 2,2-dimethyl-4-carboethoxymethyl-5-oxo-cyclobent-3-ene-1,
3-')-h Rubonic acid dimethyl ester 2,2-dimethyl-4,5-dioxo-cyclopenta7
-1.3-dicarboxylic acid dimethyl ester 25.12.
! li' and 2.25 g of carboethoxymethylenetriphenylphosphorane in chloroform 9001rLl.
Heat under reflux for 5 days.

After the reaction was completed, the reaction mixture was concentrated, 200 mJl of ether was added to the residue, and the mixture was left in a refrigerator.
After washing twice with hydrochloric acid and several times with 10% potassium carbonate aqueous solution, the ether layer was concentrated, and the residue was purified by column chromatography using silica gel to obtain 8.207 g of the target compound as an oil.

It is clear from the results of nuclear magnetic resonance spectroscopy that this substance exists as a mixture of isomers related to double bonds, and some of its carbonyl groups are in the enol type.

Infrared absorption spectrum (liquid film) ν cIrL-1:a
X 1740.1715.1655° Nuclear magnetic resonance spectrum (CDC73) δppm: 10.
2 (broad) 6.4 (doublet) 3.6-4.5 (multiplet) 1.1-1.6 (multiplet) Mass spectrum rn/e: M+= 312 Example 2 4-carboethoxy methylene-5-oxo-cyclopencune-1,3-dicarboxylic acid dimethyl ester and 4
-carboethoxymethyl-5-oxo-cyclobento-
3-ene-1,3-dicarboxylic acid dimethyl ester 4.5-dioxo-cyclopenkune-1,3-dicarboxylic acid dimethyl ester 21.417 grams Dissolved in 70% of roform 11, and this solution was dissolved in carbethoxymethylene triphenyl. Add 1.3149 phosphoranf, 2
Heat to reflux for 0 hours.

After the reaction is completed, the reaction mixture is washed with 2N hydrochloric acid, and the organic layer is extracted several times with a 5% potassium carbonate aqueous solution.

The obtained aqueous extracts were combined, washed with ether, made acidic by adding 6N hydrochloric acid under water cooling, extracted with ether, washed the ether extract with saturated brine, and anhydrous. After drying over sodium sulfate and distilling off the solvent, 22.3 g of the target compound as an oil containing crystals is obtained.

Although this oil is a mixture of isomers related to double bonds, it can be used as is as a raw material for the next step in the production of prostaglandin synthetic intermediates.

However, when this crystal-containing oil is further recrystallized using a mixed solvent of ether-〇-hexane, the melting point is 7.
11.7 g of 4-carboethoxymethylene-5-oxo-cyclopencune-1,3-dicarboxylic acid dimethyl ester are obtained as white crystals having a temperature of 3 DEG to 75 DEG C.

Infrared absorption spectrum (KBr) SimaxCrrL-
1:1745.1705.1670.1620° Nuclear magnetic resonance spectrum (CDC13) δppm: 9.9 (
IH, broad) 6.4 (LH, doublet) 4.0 to 4.4 (3H, multiplet) 3.8 (3H, -multiplet) 3.7 (3H, -multiplet) 2.4 ~3.3 (2H, multiplet) 1.3 (3H, triplet mass spectrum m/e: M+= 284 Examples
3 2-Methyl-4-carboethoxymethylene-5-oxo-cyclopencune-1,3-dicarboxylic acid dimethyl ester and 2-methyl-4-carboethoxymethyl-5
-oxo-cyclopene 1--3-1-1,3-') carboxylic acid dimethyl ester 2-methyl-4,5-dioxo-cyclopenkune-1,
6.84 g of 3-dicarboxylic acid dimethyl ester and 21. carboethoxymethylenetriphenylphosphorane.
0 g is heated under reflux in chloroform at 250 mA' for 16 hours.

After the reaction was completed, the reaction mixture was washed with 2N hydrochloric acid and then with water.
After drying with anhydrous sodium sulfate, chloroform was distilled off, the residue was dissolved in 250 m of benzef, and this solution was
Extraction is performed using a 0% potassium carbonate aqueous solution.

The resulting extracted aqueous layers were combined, washed with benzene, made acidic by adding concentrated hydrochloric acid under water cooling, extracted with ether, and washed the ether extract with saturated brine.
After drying over anhydrous sodium sulfate and distilling off the solvent, 6.4 g of the desired oily compound is obtained.

It exists as a mixture of isomers related to the double bond.

Furthermore, when this oily state is separated by column chromatography using silica gel, 2 are obtained as white crystals.
-Methyl-4-carboethoxymethylene-5-oxo-
Cyclopencune-1,3-dicarboxylic acid dimethyl ester is obtained.

Infrared absorption spectrum (KB)! , l cm-'
:r max 3400 (shoulder), 3250.1745°1
710.1680.1640.1605°Nuclear magnetic resonance spectrum (CDC13) δppm'10.0 (II-1
, - doublet) 6.4 (LH, doublet, J=3) 4.2 (3H, multiplet) 3.8 (3H, -multiplet) 3.7 (3H, -multiplet) 3. 4 (IH, double quartet) 1.3 (3H, triplet) 1.25 (3H, doublet, J=7 Mass spectrum m/e: M+= 298 Example 4 4-Carbomethoxymethylene-5 -oxo-cyclopenkune-1,2,3-tricarboxylic acid trimethyl ester and 4-carbomethoxymethyl-5-oxo-cyclobent-3-ene-1,2°3-tricarboxylic acid trimethyl ester 4,5-dioxo-cyclopenkune- 272 g of 1,2,3-tricarboxylic acid trimethyl ester was dissolved in chloroform IIH, and 66.9 g of carbomethoxymethylenetriphenylphosphorane was added to this solution, and the mixture was heated at 60°C.
Let it react for 24 hours.

After the reaction is completed, the solvent is distilled off from the reaction mixture under reduced pressure, 400 g of benzene is added and dissolved, and this solution is washed twice with 100 TL of cooled 2N hydrochloric acid.

After washing the benzene layer with water, 10% hydrium carbonate aqueous solution 2
Extract 3 times with 00ml.

The obtained extracted water layers were combined and mixed with 100wL of benzene.
After washing twice with 200ml of sodium chloride, the mixture was made acidic by adding concentrated hydrochloric acid while cooling with water, extracted three times with 200ml of ethyl acetate, the ethyl acetate extract was washed with saturated brine, and dried over anhydrous sodium sulfate. , when the solvent was distilled off, the oily target compound 26.4
g is obtained.

This oil exists as a mixture of isomers related to the double bond E.

Infrared absorption spectrum (liquid film) vmaXcrrL-1=
1750.1680.1620゜Nuclear Magnetic Resonance Spec 1 Hell (CDC73) δppm: 3
7-3.9 (multiplet) 6.4 (double line) Mass spectrum m/e: M+ = 328 Reference example 1 2.2-dimethyl-4-carboethoxymethyl-5-oxo-cyclopenkune-1,3 -dicarboxylic acid dimethyl ester 2,2-dimethyl-4-carboethoxymethylene-5-oxo-cyclopencune-1,3- obtained in Example 1
Dicarboxylic acid dimethyl ester and its geometric isomer 8
．． 209 in 50 ml methanol and 1 ml acetic acid for 10
Catalytic reduction is carried out by adding 5.0 g of palladium on carbon.

After absorbing 662 ml of hydrogen, the catalyst was separated and concentrated, and the residue was purified by column chromatography using silica gel to obtain 7.336 g of the target compound in the form of an oil.

Infrared absorption spectrum (liquid film) radiation a〆[1:1770.
1740° nuclear magnetic resonance spectrum (CDC73) δppm: 3.9
~4.4 (2H, multiplet) 2.0 ~ 3.9 (IIH, multiplet) 1.0 ~ 1.6 (9H, multiplet) Mass spectrum m/e: M+-314 reference example
2 2β-Carbomethoxy-3,3-dimethyl-5-oxo-cyclobent-1α-ylacetic acid methyl ester 2.2-dimethyl-4-carboethoxymethyl-5-oxo-cyclopentane-1,3-dicarboxylic acid dimethyl Ester 7, 34.9 was dissolved in 100ml of concentrated hydrochloric acid,
Heat to reflux for 2 hours.

After completion of the reaction, toluene was added to the reaction mixture and concentrated under reduced pressure.The remaining oil was esterified using diazomethane in a conventional manner, and the reaction product was purified by column chromatography using silica gel. As a result, 5.03 g of the target compound in the form of an oil is obtained.

Infrared absorption spectrum (liquid film) 1m a xCrn-
1:1740° nuclear magnetic resonance spectrum (CDC73) δppm'3.8
(3H, -multiple line) 3.7 (3H, -multiple line) 2.2 to 3.1 (6H, -multiple line) 1.4 (3H, -multiple line) 1.0 (3H, -multiple line ) Mass spectrum m/e: M+=242 Reference example 3 2β-carbomethoxy-3,3-dimethyl-5α-hydroxy-cyclobent-1α-ylacetic acid-γ-lactone 2β-carbomethoxy-3,3-dimethyl-5 -Oxo-cyclobent-1α-yl acetic acid methyl ester 5.5
34. Dissolve @ in anhydrous tetrahydrofuran 100,
Cool to -40°C.

To this solution, a tetrahydrofuran solution of 5ec-butylborohydride potassium having a concentration of 0.5 M/A' was added dropwise, and the mixture was further stirred at the same temperature for 30 minutes.

After the reaction is complete, 2N hydrochloric acid is added to the reaction mixture to decompose the excess boron compound, extracted with ether, and the organic layer is dried and concentrated.

The obtained residue is purified by column chromatography using silica gel to obtain 2.269 g of the target compound as crystals having a melting point of 69.5-71°C.

Infrared absorption spectrum (Nujol) Radiation aXcfIL-
1:1775.1765,1730°Nuclear magnetic resonance spectrum (CDC13) δppm=4.9
(LH, double triple line, J=6.J=8) 3.7
(3H, - multiplet) 1.5 to 3.7 (6H, multiplet) 1.3 (3H, - multiplet) 0.9 (3H, - multiplet) Mass spectrum m/e: M+ = 212 reference example
4 2β-carboxy-3,3-dimethyl-5α-hydroxy-cyclobent-1α-ylacetic acid-γ-lactone 2β-carbomethoxy-3,3-dimethyl-5α-hydroxy-cyclobent-1α-ylacetic acid-γ-lactone 2.28 g was heated under reflux in 120 ml of concentrated hydrochloric acid for 90 minutes.

After the reaction was completed, the reaction mixture was concentrated and dried under reduced pressure, and the remaining 2.05 g was recrystallized from a mixture of isopropyl ether and ethyl acetate to obtain 1.51 g of the target compound as crystals with a melting point of 179.5-181°C. It will be done.

Infrared absorption spectrum (Nujol radiation [1:1775
．． 1695.

Nuclear magnetic resonance spectrum (CD3COCD3) δppm:
8.3 (I H, broad) 5.0 (LH, double triplet) 1.6-3.7 (6H, multiplet) 1.3 (3H, -multiplet) 0.9 (3H, -multiplet) Mass spectrum m/e: M+=198 Reference example 5 2β-hydroxymethyl-3,3-dimethyl-5α-hydroxy-cyclobent-1α-ylacetic acid-γ-lactone 2β-carboxy-3,3-dimethyl-5α -Hydroxy-cyclobent-1α-ylacetic acid-γ-lactone1.
50 g of triethylamine and 1.27 ml of triethylamine were dissolved in 30 ml of dry tetrahydrofuran, and 10 ml of a dry tetrahydrofuran solution in which 0.74 ml of ethyl chlorocarbonate had been dissolved was added dropwise to this solution under ice cooling in an argon stream.

After 1 hour and 30 minutes, the triethylamine hydrochloride produced was taken from house to house and washed with 10 ml of anhydrous tetrahydrofuran, and the furnace liquid and washing liquid were added dropwise to 25 TL of an aqueous solution containing 1.14 g of sodium borohydride under ice cooling. ,Sara l
This was stirred at room temperature for 1 hour.

After the reaction was completed, the reaction mixture was made acidic by adding IN hydrochloric acid, the solvent was distilled off under reduced pressure, the residue was extracted with ethyl acetate and water, the layers were separated, and the resulting organic layer was dried. , and the residue is purified by column chromatography using silica gel to obtain 1.027 g of the target compound as an oil.

Infrared absorption spectrum (liquid film) Radiation a, cm-': 3
450, 1770.

Nuclear magnetic resonance spectrum (CDCIJ3.) δppm: 4
．． 9 (LH, multiplet) 1.1 (3H, - multiplet) 0.8 (3H, - multiplet) Mass spectrum m/e: M+-184 reference example
6 4-Carboethoxymethyl-5-oxo-cyclopencune-1,3-dicarboxylic acid dimethyl ester 4-carboethoxymethylene-5- obtained in Example 2
11.38 g of oxo-cyclopenkune-1,3-dicarboxylic acid dimethyl ester was added to 12011 IJ of methanol!
/ and catalytically reduced using 5.68 g of 5% palladium-carbon.

After the reaction is completed, the catalyst is separated and the solvent is distilled off from the reaction mixture to obtain the target compound 11.0& in the form of an oil.

Infrared absorption spectrum (liquid film) vmaxcfrL.

1765 (shoulder), 1730° nuclear magnetic resonance spectrum (CDC13) δppm'4.2
(2H, quartet) 3.8 (3H, -double 9 3.7 (3H, -double) 1.8 to 3.8 (7H, multiplet) 1.2 (3H, triplet) Reference Example 7 2-carbomethoxy-5-oxo-cyclopene 1--1
-ylacetate methyl ester 4-carboethoxymethyl-5-oxo-cyclohencun-1,3-dicarboxylic acid dimethyl ester (11.1) was dissolved in 200 ml of concentrated hydrochloric acid, heated under reflux for 4 hours, and then azeotroped with toluene to remove water. completely removed.

The remaining oil is methyl esterified using diazomethane.

After the reaction is completed, the solvent is distilled off from the reaction mixture, and the residue is distilled under reduced pressure to give a boiling point of 120-123°C10.85.
6.891 g of the target compound are obtained in the form of an oil with mmHg.

Infrared absorption spectrum (liquid film) ymaxcrrL.

1740° nuclear magnetic resonance spectrum CCDC13) δppm: 3
．． 8 (3H, - multiplet) 3.7 (3H, - multiplet) 1.7 to 3.5 (8H, multiplet) Mass spectrum m/e: M+-214 reference example 8 2β-carbomethoxy-5α- Hydroxy-cyclobent-1α-ylacetate-γ-lactone and 2α-carbomethoxy-5α-hydroxy-cyclobent-1α-ylacetate-γ-lactone 2-carbomei-xy5-oxocyclobent-1
-ylacetic acid methyl ester 6.575. Dissolve @ in 100ml of anhydrous tetrahydrofuran, and add 1l under an argon stream.
Cool on ice and hydrogenate this solution with a concentration of 0.5 M/l! 64.5 ml of a tetrahydrofuran solution of 5ec-butylboron potassium was added dropwise with stirring, and the mixture was further stirred at the same temperature for 40 minutes.

After the reaction was completed, 60 ml of 2N hydrochloric acid was added to the reaction mixture to decompose the excess boron compound, extracted with ether, the organic layer was dried, and the solvent was distilled off to give an oily crude target compound (10. ]J' is obtained.

When this is separated and purified by column chromatography using silica gel, 4.265 g of 2β-carbomethoxy compound is obtained as crystals from the less polar fraction.

When this is recrystallized from ether-n-hexane, the melting point is 4.
2.67 g of crystals with a temperature of 9.5-52° C. are obtained.

Furthermore, the 2α-carbomethoxy form is less than 0.0% from the more polar fraction.
48 g are obtained as an oil.

When this is added with 1-IJ methoxide in methanol and stirred at room temperature for 8 hours, approximately 70% of the mixture is converted to the 2β-carbomethoxy form.

2β-carbomethoxy infrared absorption spectrum (Nujol) axCrIL-1
:1755. 1740.

Nuclear magnetic resonance spectrum (CDC13) δppm: 5.0
(LH, multiplet) 3.7 (3H, -multiplet) 2α-carbomethoxy infrared absorption spectrum (liquid film) v-3, cm-': 1
770. 1730.

Nuclear magnetic resonance spectrum (CDC13) δppm: 5.8
(IH, multiplet) 3.7 (3H, - multiplet) Mass spectrum m/e: M+= 184 (2β
Reference example 9 2β-carboxy-5α-hydroxy-cyclobento
1α-ylacetic acid-γ-lactone 2β-carbomethoxy-5α-hydroxy-cyclobent-1α-ylacetic acid-
Add 2.31g of γ-lactone and 60ml of concentrated hydrochloric acid to 9
Heat to reflux for 0 minutes.

After the reaction was completed, water was distilled off from the reaction mixture under reduced pressure,
The residue was dissolved in ethyl acetate, treated with activated carbon, the solvent was distilled off, and the resulting crystals were recrystallized with ether, yielding 1.445 g of the target compound having a melting point of 101-102.5°C (decomposition). can get.

Infrared absorption spectrum (Nujol) radiation axcrrL-1
:3230. 1755. 1735.

Nuclear magnetic resonance spectrum (CD (J'3) δppm: 10
．． 2 (IH, - multiplet) 5.1 (IH, multiplet) 2.0 to 3.4 (8H, multiplet) Mass spectrum m/e: M+-170 reference example
10 2β-Hydroxymethyl-5α-hydroxy-cyclobent-1α-ylacetic acid-γ-lactone 2β-carboxy5α-hydroxy-cyclobent-1α-ylacetic acid-
1.445 g of γ-lactone and 0.0 g of triethylamine.
86g was dissolved in 40ml of dry tetrahydrofuran,
5 ml of a dry tetrahydrofuran solution containing 0.924 g of ethyl chlorocarbonate dissolved in this solution was added dropwise under water cooling, and the mixture was further cooled with ice to react for 2 hours.

After washing the precipitated triethylamine hydrochloride with tetrahydrofuran, the P solution and the washing solution were mixed with a dry methanol solution containing 0.804 g of sodium borohydride.
0 ml under water cooling, and further stirred at the same temperature for 2 hours.

After the reaction, water containing acetic acid was added to the reaction mixture, extracted with ethyl acetate, the obtained organic layer was dried and concentrated, and the residue was separated and purified by column chromatography using silica gel. 0.879 g of the methyl ester of the starting carboxylic acid was recovered, and then 0.32 g of the oily target compound was recovered from the more polar fraction. l is obtained.

Infrared absorption spectrum (liquid film) ShimaXCrIL-1
:3400.1700.1180 Nuclear magnetic resonance spectrum (CDC13) δ resuming: 5.0
(IH, multiplet) 3.6 (2H, doublet) Mass spectrum m/e2M+=156 Reference example 11 2-Methyl-4-carboethoxymethyl-5-oxo-
Cyclopencune-1,3-dicarboxylic acid dimethyl ester 2-methyl-4-carboethoxymethylene-5-oxo-cyclopencune-1,3-dicarboxylic acid dimethyl ester obtained in Example 3 and a mixture of its geometric isomers6. 4 g was dissolved in 70 ml of methanol and catalytically reduced using 4.0 g of 5% palladium-carbon.

After absorbing 518 ml of hydrogen, the catalyst was separated from the reaction mixture and the p liquid was concentrated to obtain 60 g of the target compound in the form of an oil.

Reference example 12 2-carbomethoxy-3-methyl-5-oxo-cyclobent-1-yl acetic acid methyl ester 2-methyl-4-
Carboethoxymethyl-5-oxo-cyclopenkune-
6.0 g of 1,3-dicarboxylic acid dimethyl ester was heated under reflux with 801 rL of concentrated hydrochloric acid for 3 hours to remove water completely, and the remaining oil was methyl esterified using diazomethane.

After completion of the reaction, the reaction mixture was separated and purified by column chromatography using silica gel, and the resulting oil was further distilled under reduced pressure, resulting in a boiling point of 121-130°C/1.
3.96i of the target compound is obtained in the form of an oil with 5 mmHg.

This is a five-membered [) with a trans-
It exists as a compound having trans form, cis-trans form, cis-cis form, etc., but this mixture 2.57
When 2g of sodium oxide is added to methanol and stirred at room temperature for 15 hours, the content of trans-trans isomer is 7.
Obtained 2.170g of 1% infrared absorption spectrum (liquid film) maxff-1: 7
40 Nuclear magnetic resonance spectrum (CDCI!3) δppm: 3
．． 75 (3H, -double line) 3.66 ((3H, -double line) 1.20 (double line, J=5) 1.17 (3H, double line, J=8) 0.96 (double line) Heavy line, J=7) Mass spectrum m/e: M+-228 reference example
13 2β-carbomethoxy-3α-methyl-5α-hydroxycyclobent-1α-ylacetic acid-γ-lactone 2-carbomethoxy-3-methyl-5-oxo-cyclobent-1α-ylacetic acid methyl ester 2.28 g 20mJ of anhydrous tetrahydrofuran! To this solution, 22 ml of a tetrahydrofuran solution of potassium hydride (t')-5ec-butylboron having a concentration of 0.5 M# was added dropwise with stirring.
The mixture was further stirred at the same temperature for 30 minutes.

After the reaction was completed, 40 ml of IN hydrochloric acid was added to the reaction mixture, extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off, and the resulting residue was subjected to column chromatography using silica gel. Purification by dography gives 1.342 g of the target compound as an oil.

Infrared absorption spectrum (liquid film) I-ImaxCrIL-
1:1775.1740,1735゜Nuclear magnetic resonance spectrum (CDC13) δppm'4.8
~5.2 (LH, multiplet) 3.71 (3H, - multiplet) 14 ~ 3.3 (7H, multiplet) 1.10 (3H, doublet, J=5.5) Reference example 1
4 2β-carboxy-3α-methyl-5α-hydroxy-
Cycloben-1α-ylacetate-γ-lactone 2β-carbomethoxy-3α-methyl-5α-hydroxy-cyclobent-1α-ylacetate-γ-lactone 1.
Add 120 ml of concentrated hydrochloric acid to 32 g and heat under reflux for 2 hours.

After the reaction was completed, water was distilled off from the reaction mixture under reduced pressure,
1.14 g of brown crude crystals of the target compound are obtained.

When this was recrystallized from a benzene-isopropanol mixture, the target compound with a melting point of 116-117°C was obtained.
．． 9 is obtained.

Infrared absorption spectrum (KBr)vmaXcrIL-3
440.1765.1700 Nuclear magnetic resonance spectrum (CDC13) δppm: 10
．． 73 (IH, -multiplet) 4.8-5.2 (IH, multiplet) 1.17 (3H, doublet, J=5) Mass spectrum m/e: M+184 Reference example 15 2β-hydroxymethyl- 3α-methyl-5αhydroxy-cyclobent-1α-ylacetic acid-γ-lactone 2β-carboxy3α-methyl-5α-hydroxy-
Cycloben-1α-ylacetic acid-γ-lactone 0.75
1 and triethyleneamine 0.572.9 were dissolved in 15 ml of dry tetrahydrofuran, and in an argon stream, 5 ml of a dry tetrahydrofuran solution containing 0.611 ethyl chlorocarbonate was added dropwise under ice cooling, and then React at the same temperature for 1 hour.

After washing the precipitated triethylamine hydrochloride with tetrahydrofuran, the P solution and the washing solution were added dropwise to 10 ml of an aqueous solution containing 0.64.1 ml of sodium borohydride under ice-cooling. This was allowed to react at room temperature for 1 hour.

After the reaction is completed, the reaction mixture is made acidic by adding IN hydrochloric acid, tetrahydrofuran is distilled off under reduced pressure, water is added to the residue, and the mixture is extracted with ethyl acetate.

The obtained organic layer was dried and concentrated, and the residue was purified by column chromatography using silica gel to obtain 0.552 g of the target compound in the form of an oil.

Infrared absorption spectrum (liquid film) νmax” =:
3500.1770° Nuclear magnetic resonance spectrum (CDC13) δppm'4.7
~5.1 (LH, multiplet) 3.4 ~ 4.0 (3H, multiplet) 12 ~ 3.0 (7H, multiplet) 1.07 (3H, doublet, J=6) Reference example 16 4-Carbomethoxymethyl-5-oxo-cyclopenkune-1,2,3-to IJ f)f'e I-IJ Mef
4-Carbomethoxymethylene-5-obtained in Example 4
Oxo-cyclopencune-1,2,3-tricarboxylic acid trimethyl ester and mixtures of its geometric isomers 24
．． 5! ! methanol 360 and acetic acid 1OrILl
Catalytic reduction is carried out using 24.5 I of 10-mium palladium-carbon.

After absorbing 1550 M of hydrogen, the catalyst is separated from the reaction mixture, the p liquid is concentrated, and the residue is purified by column chromatography using silica gel to obtain the target compound 18.37.9 in the form of an oil.

Infrared absorption spectrum (liquid film) radiation axCrrL-1:1
770 (shoulder), 1740° nuclear magnetic resonance spectrum (CD (J'3) δppm'3.
6-3.9 (14H, multiplet) 2.4-3.6 (4H, multiplet) Mass spectrum m/e: M+ = 330 Reference example 17 2β,3α-dicarbomethoxy-5-oxocyclobent -1α-yl acetic acid methyl ester (a) 4-carbomethoxymethyl-5-oxo-cyclopenkune-1,2
,3-1 recarboxylic acid trimethyl ester 17.63
g was heated under reflux with 260 rL of concentrated hydrochloric acid for 1.5 hours,
After completely removing water, the resulting crude crystals (14.79 g) were suspended in ether and methyl esterified using diazomecne.

After the reaction is complete, the reaction mixture is distilled under reduced pressure, resulting in a boiling point of 149
~156℃10. 126 g of the target compound are obtained in the form of an oil with O2 mmHg.

Infrared absorption spectrum (liquid film) vm, XcIrL-1=
740 Nuclear magnetic resonance spectrum (CDC13) δppm: 3.7
3 (6H, - multiplet) 3.67 (3H, - multiplet) 2.0 to 3.6 (7H, multiplet) Mass spectrum m/e: M+ = 272 (b)
4-Carbomethoxymethyl-5-oxo-cyclopenkune-1,2,3-tricarboxylic acid trimethyl ester 4
95mg and 96.5mj9 of sodium chloride in 54ml of water
Dissolve υl and 15d# of dimethyl sulfoxide, 1
Heat at 20-150°C for 4 hours.

After the reaction was completed, 307,711 liters of water was added to the reaction mixture, extracted three times with 20 ml of ether, the ether layer was dried and concentrated, and the resulting oil was purified by column chromatography using silica gel to obtain the target compound 2. 62■
is obtained.

The physical constants are those obtained by the method of Reference Example 17(a),'
matches.

Reference example '18 2β,3α-dicarbomethoxy 5α-hydroxy-cyclobent-1α-ylacetic acid-γ-lactone 2β,3α-dicarbomethoxy 5-oxocyclobent-1α-ylacetic acid methyl ester 25.88 Raney nickel (wet product 87
9 was used after washing with methanol) for catalytic reduction.

After absorbing 2,560 ml of hydrogen, the catalyst was separated, methanol was distilled off from the F solution and the washing solution, and the residue was purified by column chromatography using silica gel to obtain 21.81 g of the target compound in the form of an oil.

Infrared absorption spectrum (liquid film) radiation axCIrL-1=1
780.1730° Nuclear Magnetic Resonance Spectrum (CDC13) δppm '5.
8 (IH, multiplet) 3.7 (6H, multiplet) 2.0 to 3.4 (7H, multiplet) Mass spectrum m/e: M+ = 242 reference example
19 2β-carbomethoxy-3α-carboxy-5α-hydroxy-cyclobent-1α-ylacetic acid-γ-lactone 2β,3α-dicarbomethoxy5α-hydroxy-cycloben-1α-ylacetic acid-γ-lactone 6.06 g
was dissolved in 50 dll of methanol, and 9.45 g of barium hydroxide octahydrate was suspended in 100 dl of methanol in advance.
Add to ice-cold liquid.

Next, the reaction temperature was raised to room temperature and the reaction was carried out for 7 hours.

Then, 10% sulfuric acid was added to the reaction solution to make it acidic.
Stir for a minute to re-lactonize.

After the reaction is complete, barium sulfate is removed from the reaction mixture using Celite, the precipitate is washed with ethyl acetate, and the slurry is extracted with ethyl acetate.

The organic layer is separated, dried, and concentrated to obtain a mixture 6.29 of the oily target compound, unreacted raw material compound, and dicarboxylic acid compound that has undergone further hydrolysis.

This is purified by column chromatography using silica gel to obtain 4.09 g of the target compound in the form of an oil.

Infrared absorption spectrum (liquid film) is also aXCrrL-1:3
550 (shoulder), 3200.1770°1730
°Nuclear magnetic resonance spectrum (CD (J'3.) δppm 210.2 (IH, -multiplet) 5.0 (IH, multiplet) 3.7 (3H, -multiplet) 2.2~3. 5 (7H, multiplet) Mass spectrum r1\/e: M+ = 228 Reference example 20 2β-carbomethoxy-3α-acetyl-5α-hydroxy-cyclobent-1α-yl acetate e-γ-lactone 2β-carbomethoxy-3α After heating 4.60 g of carboxy-5α-hydroxy-cyclobent-1α-yl acetate-γ-lactone with 30 ml of thionyl chloride for 1 hour, excess thionyl chloride was distilled off at normal pressure, and then concentrated under reduced pressure. , upon drying, a crystalline acid chloride is obtained.

When this is recrystallized from benzene, the melting point is 80.5-82
．． 2.95 g of white crystals at 0° C. are obtained.

Infrared absorption spectrum (Nujo#) radiation axCrIL-1
=1790.1775.1735,635° Nuclear magnetic resonance spectrum (CDC13) δppm: 5.0 (
IH, multiplet) 3.8 (3H, - multiplet) Mass spectrum m/e: M+-246 Then, a previously prepared excess dimethyl copper lithium ether solution was added to a toluene solution 70II in which 2.88 g of acid chloride was dissolved.
The mixture was added dropwise to 60° C. over 30 minutes in L1, and reacted at the same temperature for 30 minutes.

After the reaction is complete, the reaction mixture is poured into ice water containing acetic acid and extracted with ethyl acetate.

The organic layers were combined, washed with water, dried and concentrated, and the resulting oil was purified by column chromatography using silica gel phase. The target compound 1.4 (Bi' can get.

Infrared absorption spectrum (N u 3 o /l)!
'rr* a x cIrL-': 1765.17
30.1710.

Nuclear magnetic resonance spectrum (CDC13) δppm: 5.0
(IH, multiplet) 3.7 (3H, -multiplet) 2.2 (3H, -multiplet) One mass svector m/e: M+= 226 Reference example 21 2β-carbomethoxy-3α-acetoxy-5α -hydroxy-cyclobent-1α-ylacetic acid-γ-lactone 2β-carbomethoxy-3α-acetyl-5α-hydroxy-cyclobent-1α-ylacetic acid-γ-lactone 1
．． 064g with 6.64g of sodium hydrogen phosphate
This solution was added to 301 rL of methylene chloride and cooled on ice. Peroxide was prepared by reacting 0.6381 yl A' of 90% hydrogen peroxide solution and 3.901 nl of trifluoroacetic anhydride in 20 a of methylene chloride. A fluoroacetic acid solution is added, and the mixture is further reacted at room temperature for 10 hours.

After the reaction is completed, the reaction mixture is cooled with water and added with 50 ul of 3% sodium bicarbonate solution.
In addition, the methylene chloride layers were extracted three times with 20 mA' of methylene chloride, and the methylene chloride layers were combined and washed with a trivalent aqueous sodium bicarbonate solution and an aqueous sodium thiosulfate solution, dried over anhydrous sulfuric acid, and the solvent was distilled off. , 1.077 g of crude oil is obtained.

When this oily substance is added with benzene and cooled, it crystallizes.
0.822 g of the target compound is obtained as crystals having a melting point of 86-87.5°C (in a sealed tube).

Infrared absorption spectrum (NujoA)
1:1790.1725 Nuclear magnetic resonance spectrum (CDC13) δppm: 5.4
(IH, multiplet) 5.1 (IH, multiplet) 3.7 (3H, -multiplet) 2.2 to 3.6 (6H, multiplet) 2.0 (3H, -multiplet) Mass Spectrum m/e: M+=242 Reference example 22 2β-carboxy-3α,5α-dihydroxy-cyclobent-1α-ylacetic acid-γ-lactone 2β-carbomethoxy-3α-acetoxy-5α-hydroxy-cycloben-1α-ylacetic acid - 01729 g of γ-lactone is reacted with 201111 10% hydrochloric acid at 40° C. for 5 hours.

After completion of the reaction, water is distilled off from the reaction mixture under reduced pressure and the mixture is dried to obtain 0.583 g of the target compound as crystals having a melting point of 130 to 132°C.

Infrared absorption spectrum (meItedfih)
'rIL-1=3300.1750.1710.

Nuclear magnetic resonance spectrum (CD3COCD3) δppm'
5.0 (IH, double triplet) 4.5 (IH, double triplet) Mass spectrum m/e: M+-186 reference example
23 2β-carbomethoxy-3α,5α-dihydroxy-cyclobent-1α-ylacetate-γ-lactone 2β-carboxy-3α,5α-dihydroxy-cyclobent-1α-ylacetate-γ-lactone 0.3 (Bi'
is suspended in ether and methyl esterified by adding an ether solution of diazomethane.

After the reaction is completed, the reaction mixture is purified by column chromatography using silica gel to obtain the target compound 0.244 F as crystals having a melting point of 66-68°C.

Infrared absorption spectrum (CHC7, solution) νmax"-
1:3450.1765.1730.

Nuclear magnetic resonance spectrum (CDC13) δppm '5.
0 (IH, multiplet) 4.5 (LH, double triplet) 3.7 (3H, -multiplet) 3.6 (IH, -multiplet)

Claims (1)

[Claims] Formula 1 (wherein R1 represents a hydrogen atom or a lower alkyl group)
R2 represents a hydrogen atom, a lower alkyl group or a lower alkoxycarbonyl group, and R3 represents a lower alkyl group. ) is reacted with a Witzig reagent having the formula % (wherein R4 represents a lower alkyl group and R5 represents a lower alkyl group or an aryl group), and if necessary, the resulting compound is separated. A formula characterized by the following (in the formula, R
1, R2, R3 and R4 have the same meanings as described above. ) A method for producing a cyclopentanone carboxylic acid ester derivative.