JP3340732B1 - Method for producing cyclopentabenzofuran derivative and novel compound as raw material for production - Google Patents

Abstract

A cyclopentabenzofuran derivative (α, β-unsaturated ketone) required for the synthesis of beraprost sodium
It is an object of the present invention to provide a high-yield production method that can safely react under mild conditions in place of the Wordsworth reaction. SOLUTION: A 3-methyl-2-oxo-5-heptynylidene-trialkyl (or triaryl) phosphorane is produced using 3-methyl-2-oxo-5-heptynyl chloride, and this phosphorane compound is used. To produce a cyclopentabenzofuran derivative.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel method for producing a cyclopentabenzofuran derivative which is an intermediate in the synthesis of beraprost sodium, a novel chloro compound used for the production, and a novel phosphorane compound.

[0002]

2. Description of the Related Art Beraprost sodium is known as a stable prostaglandin I ₂ (PGI ₂ ) derivative which can be administered orally, and is a compound useful as a therapeutic drug for intractable arterial blood flow disorders such as chronic arterial occlusion. As a method for producing beraprost sodium, the method shown in Scheme 1 is described as a specific example in Japanese Patent Publication No. 1-53672 and Japanese Patent Publication No. 3-69909.

[0003]

Embedded image That is, an aldehyde compound synthesized from a diol compound is converted into an α, β-unsaturated ketone compound (cyclopentabenzoheran derivative) by a Wordsworth reaction, and then reduced to beraprost sodium by hydrolysis. In this method, the process for producing an α, β-unsaturated ketone is an important process in which an ω chain having an acetylene bond specific to beraprost sodium is formed. In this process, a Wordsworth reagent is converted to sodium hydride, alkyl lithium Active anions using a strong base such as aryl lithium, potassium hydride or the like, and reacting this anion with an aldehyde compound. However, the strong base reagent used is extremely reactive and is not only easily deactivated by moisture absorption, but also generates hydrogen gas and flammable gas, which is dangerous. In addition, since it has irritation to the skin and the like, it is necessary to take great care in handling. Furthermore, since the anions of the Wordsworth reagent generated in the reaction solution are also highly reactive, moisture causes a reduction in the reaction yield, and therefore, this reaction must be performed in an inert gas such as argon. Further, the Wordsworth reagent necessary for this reaction is not easily available from the market, and the method shown in the following scheme 2 described as a specific example in Japanese Patent Publication No. 1-53672, that is, dimethyl methanephosphonate has a strong base N-butyllithium at −78 ° C. to form a lithium salt, and then react with 2-methyl-4-hexanoic acid methyl ester at the same temperature to separately produce the salt.

[0004]

Embedded image As described above, the above method using the Wordsworth reaction has disadvantages such as the use of strong bases such as sodium hydride and n-butyllithium which are difficult to handle many times, and the necessity of a reaction at an extremely low temperature of −78 ° C. Many.

[0005]

SUMMARY OF THE INVENTION The present invention relates to a process for producing a cyclopentabenzofuran derivative (α, β-unsaturated ketone) required for the synthesis of beraprost sodium, which can be safely performed under mild conditions instead of the Wordsworth reaction. The object of the present invention is to provide a production method which can be reacted and has a high yield.

[0006]

Means for Solving the Problems The present inventors have intensively studied to develop a simple and excellent manufacturing method in order to solve these problems of the above-mentioned conventional manufacturing method. As a result, a method for synthesizing a phosphoryl compound (3), which is a novel Wittig reagent shown below, from a novel chloro compound (4) was developed, and a Wittig reaction (Wittigr) using this compound was developed.
eaction) to successfully produce the desired cyclopentabenzofuran derivative (α, β-unsaturated ketone) (1), thereby completing the present invention. Phosphorane compound (3) is a very stable reagent and easy to handle,
The reaction does not require the conversion to an anion, which requires a high degree of control, unlike the Wordsworth reagent in the conventional method, and can be converted to the desired product in a very high yield simply by simply mixing with the aldehyde compound (2). It has a very good advantage.

That is, the present invention provides the following equation (2)

Embedded image Wherein R ₁ represents hydrogen or a protecting group for a hydroxyl group, and an aldehyde compound represented by the formula (3):

Embedded image Wherein R ₂ represents an alkyl group or an aryl group, wherein the compound is reacted with a phosphorane compound represented by the formula (1):

Embedded image A method for producing a cyclopentabenzofuran derivative represented by the formula: (Wherein R ₁ is the same as defined above) and the formula (3)

Embedded image (Wherein, R ₂ represents an alkyl group or an aryl group), and succeeded in synthesizing a phosphorane compound represented by the following formula:

Formula (4) Has been successfully synthesized.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION In the embodiment of the present invention, as a protecting group for a hydroxyl group in R ₁ of a cyclopentabenzofuran derivative (1) and an aldehyde compound (2), an acyl group such as an acetyl group and a propionyl group, and a benzoyl group And the like, an aroyl group, a t-butyl group, a tetrahydropyranyl group, a tri-substituted silyl group and the like. Examples of the alkyl group for R ₂ in the phosphorane compound (3) include linear, branched, or cyclic alkyl, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, and cyclohexyl. Group, octyl group, decyl group and the like, and preferably butyl group and cyclohexyl group. As the aryl group, a phenyl group,
Examples include a substituted phenyl group. Examples of the substituent of the phenyl group include a methyl group, chloro, bromo, nitro, and methoxy group. Preferred examples of the aryl group include a phenyl group. Hereinafter, the present invention will be described specifically.

Novel Method for Producing Cyclopentabenzofuran Derivative (1) The aldehyde compound (2), which is a starting compound of the present invention, is a known compound and is described, for example, in Japanese Patent Publication No. 1-53672 or Japanese Patent Publication No. 3-69909. It can be manufactured by the following method. The cyclopentabenzofuran derivative (1) according to the present invention can be produced by a Wittig reaction of the aldehyde compound (2) with a phosphorane compound represented by the formula (3), which is a novel compound of the present invention. The amount of the phosphorane compound (3) to be used is 1 to 3 equivalents, preferably 1 to 1.5 equivalents, to the aldehyde compound (2). The solvent used in the reaction is not particularly limited, but includes, for example, methylene chloride, chloroform, ether, tetrahydrofuran, dimethoxyethane, dioxane, ethyl acetate, hexane, benzene, dimethylformamide, and preferably ether, dimethoxyethane, and tetrahydrofuran. And two or more of them can be used in combination. The amount of the solvent used is 5 to 100 times the volume of the aldehyde compound (2), preferably 10 to 10 times.
Up to 20 times the volume. The Wittig reaction has a different reaction rate depending on the type of the substituent R ₂ in the phosphorane compound (3). The reaction is carried out at a temperature of -10 to 100 ° C, preferably under water cooling or at room temperature, and the reaction time is 1 hour to 5 days, preferably 2 hours to 4 days. The target compound can be isolated by concentrating the reaction solution under reduced pressure and purifying the resulting residue by silica gel column chromatography to obtain the target compound cyclopentabenzofuran derivative (1).

Method for producing novel phosphorane compound (3) The novel phosphorane compound (3) of the present invention is 3-methyl-2
The novel chloro compound (4) produced from -oxo-5-heptin [compound (b)] is produced as an intermediate by the route shown in Scheme 3.

Embedded image

Method for producing 3-methyl-2-oxo-5-heptin [compound (b)] Compound (b) is converted to ethyl 2-methylacetoacetate as shown in Reaction Scheme 1) in Scheme 3 to give ethanol. Medium, 1-bromo-2 using sodium ethylate
-Butyne compound (a) is reacted, then hydrolyzed with a dilute aqueous sodium hydroxide solution represented by reaction formula 2), and then decarboxylated. Concentrate the reaction mixture, extract,
The residue obtained after drying and concentration can be purified by distillation under reduced pressure.

Method for producing 3-methyl-2-oxo-5-heptinyl chloride [chloro compound (4)] First, as shown in reaction formula 3), aminoethanol is added to compound (b) 1 to 20 times. Add an equivalent, preferably 5 to 10 times equivalent. In the reaction, a solvent azeotropic with water, such as benzene, toluene, or xylene, is used to remove generated water, but toluene is preferred. The amount of the solvent to be used is 5-200 times, preferably 10-50 times, the volume of compound (b). The reaction temperature is preferably a reflux temperature, and the reaction is carried out while attaching a water separator to separate generated water. The reaction time is 1 to 48 hours, preferably 8 to 24 hours.
Time. In the reaction, an appropriate catalyst is used to promote the dehydration reaction. For example, a cation exchange resin (carboxylic acid type, sulfonic acid), preferably a sulfonic acid type ion exchange resin is used. The amount of use is 0.01 to 1 times (w / w), preferably 0.1 to 0.5 times the amount of compound (b). The formation of the imine compound (c) thus obtained is almost quantitative. The catalyst is removed by filtration, the solvent and excess aminoethanol are distilled off, and then used for the next step reaction without purification.

Next, the imine compound (c) is subjected to dichlorination as shown in the reaction formula 4). The chlorination can be carried out in a suitable solvent using a chlorinating agent such as sulfuryl chloride or N-chlorosuccinimide. The chlorinating agent is used in an amount of 1.5 to 5 equivalents, preferably 2 to 3 equivalents, based on the imine compound (c). The solvent is not particularly limited, but includes, for example, ether, dimethoxyethane, tetrahydrofuran, dioxane, methylene chloride, and chloroform. Preferably, ether, dimethoxyethane, tetrahydrofuran or a mixed solvent can be used. The amount of the solvent to be used is 5 to 100 times, preferably 10 to 50 times, the volume of the imine compound (c). The reaction temperature is -10 to 100 ° C, preferably 0 to 50 ° C, and the reaction time is 1 to 48 hours, preferably 5 to 18 hours. The hydrolysis is carried out after the completion of the halogenation reaction. Usually, after the completion of the halogenation reaction, the reaction can be carried out by adding an appropriate acid to the reaction solution. The acid to be used includes, for example, hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid and the like, and preferably, hydrochloric acid and sulfuric acid. 0.05 to these acids
It is used as a 5N, preferably 0.1-1N aqueous solution.
The reaction temperature is -10 to 50 ° C, preferably 0 ° C to room temperature,
The reaction time is 30 minutes to 24 hours, preferably 1 to 5 hours. The resulting dichloride (d) is used for the next reaction without purifying the residue obtained by extracting, drying and concentrating the reaction solution.

Next, the dichloro compound (d) is reduced to a chloro compound (4) which is a monochloro compound. Dichlor body (d)
Is reduced to a monochloro form by using zinc / acetic acid in an appropriate solvent as shown in the reaction formula 5). Although the solvent used in the reaction is not particularly limited, for example, methylene chloride,
Chloroform, ether, tetrahydrofuran, dioxane, ethyl acetate, hexane, benzene, dimethylformamide are preferable, and ether is preferable. The solvent is used in an amount of 5 to 100 times, preferably 10 to 50 times the volume of the crude dichloride (d). Zinc is usually used in the form of powder, but the amount of zinc used is 0.5 to 20 times the amount of the crude dichloride (d), preferably 1 to 1 times.
Use 0 times (w / w). The amount of acetic acid used is 1 to 20 times, preferably 5 to 10 times the volume of the crude weight of the dichloro compound (d). Reaction temperature is -30 to 50 ° C, preferably -20 ° C to
Room temperature, the reaction time is 2 to 36 hours, preferably 4 to 24 hours.
Time. The target compound is obtained by neutralizing acetic acid after completion of the reaction, extracting the insoluble matter by filtration, extracting the residue, drying and concentrating the residue under reduced pressure, or purifying the residue by silica gel column chromatography, or distilling it under reduced pressure by distillation under reduced pressure. Compound (4) can be obtained.

Preparation of 3-methyl-2-oxo-5-heptynyl-trialkyl (or triaryl) phosphonium chloride [compound (e)] The phosphonium compound (e) is prepared by using a suitable solvent as shown in Reaction Scheme 6). The compound is obtained by reacting a chloro compound (4) with a trialkylphosphine or a triarylphosphine. The amount of the phosphine compound to be used is 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to chloro compound (4). The solvent is not particularly limited as long as it does not react with the chloro compound (4), but includes tetrahydrofuran, ether, dioxane, methylene chloride, chloroform and the like, and preferably includes ether and chloroform. The amount of the solvent used is 5 with respect to the chloro compound (4).
The volume is up to 100 times, preferably 5 to 20 times. The reaction temperature is 0 ° C to 100 ° C, preferably room temperature to 60 ° C. The reaction time is 30 minutes to 48 hours, preferably 1 to 20 hours. When the target compound is a crystal, the precipitated crystal can be purified by filtering and recrystallizing, but the resulting phosphonium compound (e) can be used as it is in the next step.

Preparation of 3-methyl-2-oxo-5-heptinylidene-trialkyl (or triaryl) phosphorane [phosphorane compound (3)] Phosphorane compound (3) from phosphonium compound (e)
The conversion to can be carried out by treating the phosphonium compound (e) with a base as shown in Reaction formula 7). Although a solvent is used in the reaction, there is no particular limitation as long as it does not hinder the reaction, for example, acetonitrile,
Examples thereof include methylene chloride, chloroform, tetrahydrofuran, dioxane, methanol, and ethanol, and preferably include methylene chloride and chloroform. The amount of the solvent used is 5 to 5% based on the phosphonium compound (e).
The volume is 100 times, preferably 10 to 20 times. Examples of the base used include sodium hydrogencarbonate, sodium carbonate, potassium carbonate, caustic soda, caustic potash, triethylamine, pyridine and the like, and preferably sodium carbonate and potassium carbonate. The base is usually used as an aqueous solution, and its concentration is 1 to 50% (w / v), preferably 5 to 10%. Reaction temperature is 0
C. to 50.degree. C., preferably 0.degree. C. to room temperature.
Minutes to 24 hours, preferably 30 minutes to 5 hours. After the reaction, the target substance is extracted, dried and concentrated, and the resulting residue can be purified by silica gel column chromatography or the like, but the resulting phosphorane compound (3) can be used as it is in the next step.

[0017]

EXAMPLES Hereinafter, the present invention will be described more specifically, but the present invention is not limited to these examples.

Example 1 Method for producing 3-methyl-2-oxo-5-heptin 5.2 g of sodium ethoxide was dissolved in 100 ml of anhydrous ethanol, and 9.6 g of ethyl 2-methylacetoacetate was added at room temperature for 1 hour. Stirred. Next, 8.5 g of 1-bromo-2-butyne was added to the solution under water cooling, and the mixture was stirred at room temperature for 3 hours. The reaction solution was heated to 50 ° C., 48 ml of a 2N aqueous sodium hydroxide solution was added, and the mixture was heated under reflux for 3 hours. After cooling, cold water 2
The mixture was poured into 50 ml and extracted three times with 100 ml of ethyl ether. The organic layers were combined, washed with saturated saline, dried and concentrated, and the resulting oil was distilled under reduced pressure to give the title compound as a colorless oil (5.2 g, yield 65%). %).

Bp30 80-89 ° C IR (ν, neat, cm ⁻¹ ) 2974, 2923, 1714, 1459,
1431, 1326, 11790 MHz NMR (CDCl ₃ , δppm) 1.18
(3H, d, J = 6.9Hz), 1.76 (3H, t, J = 2.5Hz),
2.19 (3H, s), 2.13 to 2.42 (2H, m), 2.67 (1H, 6
Heavy line, J = 6.9Hz)

Example 2 Method for producing 3-methyl-2-oxo-5-heptynyl chloride 2.48 g of 3-methyl-2-oxo-5-heptin was dissolved in 100 ml of toluene, and a sulfonic acid type ion exchange resin ( Dowex
50W) 0.6 g and ethanolamine 12.2 g were added, and the mixture was heated and refluxed for 8 hours while azeotropically removing generated water. After the solid was filtered off, the reaction solution was concentrated under reduced pressure to obtain a yellow oily imine compound. This was dissolved in 80 ml of tetrahydrofuran, 5.3 g of N-chlorosuccinimide was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was ice-cooled, 60 ml of 0.5N hydrochloric acid was added, and the mixture was stirred for 1 hour, and then poured into 200 ml of cold water. The mixture was extracted three times with 100 ml of ethyl ether. The organic layers were combined, washed with water and saturated saline, dried and concentrated to obtain a dichloro compound. This dichloride was dissolved in 100 ml of ethyl ether, and 3.0 g of zinc was dissolved.
And then cooled to -20 ° C. Acetic acid with stirring at the same temperature
7.5 ml was added dropwise and reacted at -10 ° C for 3 hours. Next, 120 ml of a 10% aqueous solution of sodium bicarbonate was carefully added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. Then, the solid matter was separated by filtration and washed with ethyl ether. The organic layer was separated, the aqueous layer was further extracted with 50 ml of ethyl ether, and the organic layers were combined, washed with water and saturated saline, and then washed.
Drying and concentration gave 3.0 g of a crude oil. This was purified by silica gel column chromatography (hexane: ether = 20: 1) to obtain 2.25 g (yield: 71%) of the title compound as a colorless oil.

IR (ν, neat, cm ⁻¹ ) 2976, 2923,
1734, 1458, 1033, 770 90 MHz NMR (CDCl ₃ , δ ppm) 1.21 (3H, d, J = 6.9H
z), 1.76 (3H, t, J = 2.5 Hz), 2.22 to 2.46 (2H, m
), 2.98 (1H, hex, J = 6.9 Hz), 4.23 (2H, s
)

Example 3 Method for producing 3-methyl-2-oxo-5-heptynyl-triphenylphosphonium chloride 317m of 3-methyl-2-oxo-5-heptynyl chloride
g was dissolved in 3.5 ml of chloroform, 577 mg of triphenylphosphine was added, and the mixture was heated under reflux with stirring for 18 hours. After cooling, 15 ml of ethyl ether was added to the solidified reaction mixture, and the mixture was stirred for 30 minutes. The crystals were collected by filtration, washed with ethyl ether, and dried in vacuo to give 820 mg of the title compound as white crystals (yield 97%).
%).

Mp 196-199 ° C IR (ν, KBr, cm ⁻¹ ) 2971, 2918, 2765, 1700, 1
438, 1361, 1113, 754, 693 90 MHz NMR (CDCl ₃ , δ ppm) 1.20 and 1.36 (3H, d ×
2, J = 6.9Hz), 1.64 (3H, t, J = 2.5Hz), 2.14 ~
2.86 (2H, m), 3.17 to 3.60 (1H, m), 4.52 to 6.95
(2H, m), 7.48 to 8.10 (15H, m),

Example 4 Process for producing 3-methyl-2-oxo-5-heptynyl-tributylphosphonium chloride 310 m 3-methyl-2-oxo-5-heptynyl chloride
g was dissolved in 5 ml of chloroform, 395 mg of tri-n-butylphosphine was added, and the mixture was heated under reflux with stirring for 14 hours. After cooling, the reaction solution was concentrated under reduced pressure to give the title compound as a colorless oil (703m)
g (100% yield) was obtained.

IR (ν, neat, cm ⁻¹ ) 3419, 2962, 2
935, 2875, 1708, 1628, 1460, 1029 90MHz NMR (CDCl 3, δppm) 0.77~1.10 (9H, m),
1.26 (3H, d, J = 6.9Hz), 1.31 to 1.75 (12H, m),
1.74 (3H, t, J = 2.5Hz), 2.19 to 2.68 (6H, m),
3.04 (1H, hex, J = 6.9Hz), 4.43 and 5.04 (1H
× 2, dd, J = 18.2Hz, 12.8Hz)

Example 5 Method for producing 3-methyl-2-oxo-5-heptynylidene-tributylphosphorane 703 mg of 3-methyl-2-oxo-5-heptynyl-tributylphosphonium chloride was dissolved in 10 ml of chloroform, and the solution was added at room temperature. 6 ml of a 10% aqueous potassium carbonate solution was added, and the mixture was stirred for 1 hour. After separating the organic layer, the aqueous layer is further chloroform 5m
The mixture was extracted with 1, and the organic layers were combined and washed with water and saturated saline. The oily substance obtained by drying and concentration under reduced pressure was subjected to silica gel column chromatography (chloroform: methanol = 20: 1).
620 mg (98% yield) of the title compound as a yellow oil
I got

MS (Fab, [M + H] ⁺ m / z) 325 IR (ν, neat, cm ⁻¹ ) 2960, 2931, 2875, 1527,
1459, 1407, 1096, 914 90MHz NMR (CDCl3, δ ppm) 0.93 (9H, t, J = 6.0H
z), 1.15 (3H, d, J = 6.0Hz), 1.25 to 2.95 (22H, m
), 1.76 (3H, t, J = 2.5Hz)

Example 6 Method for producing 3-methyl-2-oxo-5-heptynylidene-triphenylphosphorane 700 mg of 3-methyl-2-oxo-5-heptynyl-triphenylphosphonium chloride was dissolved in 10 ml of chloroform, and the solution was stirred at room temperature. 6 ml of a 10% aqueous potassium carbonate solution was added thereto, and the mixture was stirred for 1 hour. After separating the organic layer, the aqueous layer is further chloroform
The mixture was extracted with 5 ml, and the organic layers were combined and washed with water and saturated saline. The oily substance obtained by drying and concentration under reduced pressure was subjected to silica gel column chromatography (chloroform: methanol = 30:
Purify in 1) to give the title compound (632 mg, yield 99) as an orange oil.
%).

MS (Fab, [M + H] ⁺ m / z) 385 IR (ν, neat, cm ⁻¹ ) 3058, 2963, 2918, 1538,
1438, 1397, 1108, 874, 748 90MHz NMR (CDCl 3, δppm) 1.23 (3H, d, J = 6.7H
z), 1.79 (3H, t, J = 2.5 Hz), 1.98 to 2.65 (3H, m
), 2.95 to 3.20 (1H, br), 7.32 to 7.84 (15H, m
)

Example 7 11,15-Dideoxy-11-acetoxy-16-methyl-15-oxo-18,19-tetradehydro-
3-Methyl-2-oxo-5 of 5,6,7-trinor-4,8-inter-m-phenylene PGI _2- methyl ester
Production Method Using Heptynylidene-Tributylphosphorane 4- [2-Endo-acetoxy-1-exo-hydroxymethyl-3a, 8b-cis-2,3,3a, 8b-tetrahydro-1H-5-cyclopenta [b] [Benzofuranyl] butyrate 669mg in anhydrous benzene 7ml solution pyridine 0.23ml
Then, a solution of 0.12 ml of trifluoroacetic acid in 7 ml of anhydrous DMSO was added, and then 650 mg of dicyclohexylcarbodiimide was added, followed by stirring at room temperature for 15 hours. The deposited precipitate is separated by filtration,
After washing with benzene, the filtrate was washed with water, and the obtained organic layer was dried and concentrated under reduced pressure to obtain a crude aldehyde. This was dissolved in 8 ml of dimethoxyethane, and a solution of 750 mg of 3-methyl-2-oxo-5-heptynylidene-tributylphosphorane in 5 ml of dimethoxyethane was added, followed by stirring at room temperature for 3 hours. After the reaction solution was concentrated under reduced pressure, the obtained oil was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain 620 mg (yield: 72%) of the title compound as a yellow oil.

IR (ν, neat, cm ⁻¹ ) 2946, 1733, 1
455, 1373, 1240, 1048 90 MHz NMR (CDCl ₃ , δ ppm) 1.21 (3H, d, J = 6.9H
z), 1.70-1.84 (6H, m), 1.86-3.16 (12H, m),
3.66 (3H, s), 3.58 to 3.79 (1H, m), 5.01 (1
H, q, J = 5.9Hz), 5.13 to 5.38 (1H, m), 6.28 (1
H, d, J = 15.9 Hz), 6.65 to 7.05 (4H, m) Similarly, 4- [2-endo-hydroxy-1-exo-hydroxymethyl-3a, 8b-cis-2,3,3a, 8b- Using methyl tetrahydro-1H-5-cyclopenta [b] benzofuranyl] butyrate and 3-methyl-2-oxo-5-heptynylidene-tributylphosphorane gives 15-deoxy-16-methyl-15-oxo-18,19-. Tetradehydro-5,6,7-trinor-4,8-inter-m-phenylene PGI _2- methyl ester can be obtained.

IR (ν, neat, cm ⁻¹ ) 3457, 2934, 1
737, 1694, 1625, 1453, 1257,1193 90MHz NMR (CDCl 3, δppm) 1.21 (3H, d, J = 6.9H
z), 1.6 (3H, t, J = 2.5Hz), 1.77-3.09 (13H, m
), 3.65 (3H, s), 3.44 to 3.68 (1H, m), 4.10
(1H, brq, J = 6.7Hz), 5.02 to 5.28 (1H, m), 6.
32 (1H, d, J = 15.6Hz), 6.65 to 7.04 (4H, m)

Example 8 11,15-Dideoxy-11-acetoxy-16-methyl-15-oxo-18,19-tetradehydro-
3-Methyl-2-oxo-5 of 5,6,7-trinor-4,8-inter-m-phenylene PGI _2- methyl ester
Production Method Using Heptynylidene-Triphenylphosphorane 4- [2-Endo-acetoxy-1-exo-hydroxymethyl-3a, 8b-cis-2,3,3a, 8b-tetrahydro-1H-5-cyclopenta [b ] [Benzofuranyl] 0.10 ml of pyridine in a solution of 481 mg of methyl butyrate in 5 ml of anhydrous benzene
Then, a solution of 0.05 ml of trifluoroacetic acid in 5 ml of anhydrous DMSO was added, and then 470 mg of dicyclohexylcarbodiimide was added, followed by stirring at room temperature for 16 hours. The deposited precipitate is separated by filtration,
After washing with benzene, the filtrate was washed with water, and the obtained organic layer was dried and concentrated under reduced pressure to obtain a crude aldehyde. This was dissolved in 6 ml of dimethoxyethane, and 630 mg of 3-methyl-2-oxo-5-heptynylidene-triphenylphosphorane was dissolved.
Was added and the mixture was stirred at room temperature for 50 hours. After the reaction solution was concentrated under reduced pressure, the resulting oil was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1).
471 mg (75% yield) of the title compound as a yellow oil
I got

IR (ν, neat, cm ⁻¹ ) 2946, 1733, 1
455, 1373, 1240, 1048 90 MHz NMR (CDCl ₃ , δ ppm) 1.21 (3H, d, J = 6.9H
z), 1.70-1.84 (6H, m), 1.86-3.16 (12H, m),
3.66 (3H, s), 3.58 to 3.79 (1H, m), 5.01 (1
H, q, J = 5.9Hz), 5.13 to 5.38 (1H, m), 6.28 (1
H, d, J = 15.9Hz), 6.65-7.05 (4H, m)

──────────────────────────────────────────────────続 き Continuation of the front page (56) References JP-A-58-124778 (JP, A) JP-A-59-134787 (JP, A) JP-A-54-27556 (JP, A) International publication 90/10003 (WO, A1) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07F 9/535 C07C 49/227 C07D 307/93 CAPLUS (STN) REGISTRY (STN)

Claims (3)

(57) [Claims] (1) The following formula (2): (Wherein R ₁ represents a protecting group for hydrogen or a hydroxyl group) and an aldehyde compound represented by the following formula (3): (Wherein R ₂ represents an alkyl group or an aryl group) characterized by reacting with a phosphorane compound represented by the following formula (1): (Wherein R ₁ represents hydrogen or a protecting group for a hydroxyl group). 2. The following formula (3): (Wherein R ₂ represents an alkyl group or an aryl group). 3. The following formula (4): A chloro compound as a raw material for obtaining a phosphorane compound represented by the formula (3) according to claim 2 represented by the formula: