JP2893883B2 - Method for producing acetylenedicarboxylic acid ester - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> The present invention relates to a method for producing an acetylenedicarboxylic acid ester which is useful as an intermediate for producing pharmaceuticals, particularly prostaglandins.

<Prior art> General formula [I] (In the formula, R represents a C ₁ -C ₆ alkyl group.) The following two production methods are known as methods for obtaining an acetylenedicarboxylic acid ester represented by the following formula:

Production method by metathesis reaction (Tetrahedron Letters, 23
(49), p.5139-5140 (1982)) Production method using diethyl malonate (Journal of Chemica
l Society, p.3208 (1954)) However, these methods have drawbacks such as difficulty in synthesizing the raw materials to be used, and the other methods have many disadvantages such as a large number of steps, and none of these methods are industrially satisfactory.

<Problems to be Solved by the Invention> From the above, the present inventors have intensively studied a more industrially advantageous method in order to solve the above-mentioned problems, and as a result, have reached the present invention.

<Means for Solving the Problems> That is, the present invention relates to a method for producing an acetylenedicarboxylic acid ester represented by the general formula [I].

 Hereinafter, the present invention will be described in detail.

The acetylenedicarboxylic acid ester represented by the general formula [I] is represented by the general formula [IV] (Wherein X ¹ and X ² each represent a chlorine atom, a bromine atom, an iodine atom, a methanesulfonyloxy group or a p-toluenesulfonyloxy group); and an acetylene derivative represented by the general formula [III]: (Wherein, R represents the same meaning as described above.) In the presence of metal alkoxides. Further, an acetylene derivative represented by the general formula (IV) and a general formula (II)
With an acetoacetate ester represented by the formula (II) (Wherein, R represents the same meaning as described above). An acetoacetic acid derivative represented by the following formula is obtained, and the reaction can be further carried out in the presence of a metal alkoxide to produce the derivative.

An acetylene derivative represented by the general formula [IV] and an acetoacetic ester represented by the general formula [III] are reacted in the presence of a metal alkoxide to form the general formula [I]
In the production of the acetylenedicarboxylic acid ester represented by the acetylene derivative [IV] used,
4-dichloro-2-butyne, 1,4-dibromo-2-butyne, 1,4-diiodo-2-butyne, 1,4-dimethanesulfonyloxy-2-butyne, 1,4-dip-toluenesulfonyl Oxy-2-butyne, 1-bromo-4-chloro-2
-Butyne, 1-chloro-4-iodo-2-butyne, 1-
Bromo-4-iodo-2-butyne and the like can be mentioned.

Acetoacetates used in this reaction [II
I], methyl acetoacetate, ethyl acetoacetate,
Examples thereof include n-propyl acetoacetate, isopropyl acetoacetate, n-butyl acetoacetate, n-pentyl acetoacetate, and n-hexyl acetoacetate. Carbon number 7
Although the use of the above acetoacetates does not cause any problem, it is disadvantageous in cost.

Examples of the metal alkoxide used in this reaction include sodium methoxide, sodium ethoxide, potassium methoxide, potassium t-butoxide and the like.

Acetylene derivatives [IV], acetoacetates [II
The method of charging I] and metal alkoxides is not particularly limited. Further, metal alkoxides can be added during the reaction as needed.

The solvent for this reaction can be added as needed as long as it does not inhibit the reaction. For example, aromatic solvents such as benzene, toluene and xylene, hydrocarbon solvents such as pentane and hexane, ester solvents such as methyl acetate and ethyl acetate, alcohol solvents such as methanol and ethanol, diethyl ether, diisopropyl ether and the like Ether solvents and the like, and these solvents can be mixed and used at an arbitrary ratio.

The amount of the acetoacetates [III] used in this reaction is 1 to 10 times, and usually 2 to 4 times, the mol of the acetylene derivative [IV].

The amount of the metal alkoxide to be used is 0.5 to 10 moles, usually 1 to 4 moles per mole of the acetoacetate ester [III].

The reaction temperature of this reaction may be 20 ° C or higher, and is usually 50 ° C.
Performed at ~ 150 ° C.

 The reaction time is not particularly limited.

After completion of the reaction, an acetylenedicarboxylic acid ester represented by the general formula [I] is obtained by usual post-treatments such as solvent evaporation, washing, extraction and concentration, and can be purified by distillation under reduced pressure.

In the production of an acetoacetic acid derivative represented by the general formula (II) by reacting an acetylene derivative represented by the general formula (IV) and an acetoacetic ester represented by the general formula (III) in the presence of carbonates, The same acetylene derivative [IV] and acetoacetic esters as those used in the above reaction are used.

The carbonates used in this reaction include potassium carbonate, sodium carbonate and the like.

Acetylene derivatives [IV], acetoacetates [II
The method for preparing I] and the carbonates is not particularly limited.
Further, carbonates can be added during the reaction, if necessary.

The solvent for this reaction can be added as needed as long as it does not inhibit the reaction. For example, aromatic solvents such as benzene, toluene and xylene, hydrocarbon solvents such as pentane and hexane, ester solvents such as methyl acetate and ethyl acetate, alcohol solvents such as methanol and ethanol, diethyl ether, diisopropyl ether and the like Ether solvents and the like, and these solvents can be mixed and used at an arbitrary ratio.

The amount of the acetoacetates [III] used in this reaction is 1 to 10 times, and usually 2 to 4 times, the mol of the acetylene derivative [IV].

The amount of the carbonate to be used is 0.5 to 10 times mol, usually 1 to 4 times mol for acetoacetic ester [III].

The reaction temperature of this reaction may be 20 ° C or higher, and is usually 50 ° C.
Performed at ~ 150 ° C.

The reaction time is not particularly limited, and an acetylene derivative (IV)
Can be regarded as the end point of the reaction when no is detected from the reaction system.

After completion of the reaction, an acetoacetic acid derivative represented by the general formula [II] is obtained by usual post-treatments such as filtration, solvent evaporation, washing, extraction, and concentration, and can be purified by distillation under reduced pressure.

In the production of the acetylenedicarboxylic acid ester represented by the general formula [I] by reacting an acetoacetic acid derivative represented by the general formula [II] in the presence of a metal alkoxide, sodium methoxide is used as the metal alkoxide used. Sodium ethoxide, potassium methoxide, potassium t-butoxide and the like can be mentioned.

The method of charging the acetoacetic acid derivative [II] and the metal alkoxides is not particularly limited. Further, metal alkoxides can be added during the reaction as needed.

The amount of the metal alkoxide used in this reaction is 0.01 to 10 moles, preferably 0.1 to 1 mole, relative to the acetoacetic acid derivative [II].

The solvent for this reaction can be added as needed as long as it does not inhibit the reaction.Examples include aromatic solvents such as benzene, toluene, and xylene, hydrocarbon solvents such as pentane and hexane, methyl acetate, and acetic acid. Examples thereof include ester solvents such as ethyl, alcohol solvents such as methanol and ethanol, and ether solvents such as diethyl ether and diisopropyl ether. These solvents may be used in a mixture at any ratio.

The reaction temperature of this reaction may be 0 ° C. or higher, and is usually 20 ° C.
Performed at ~ 100 ° C.

The reaction time is not particularly limited, and the acetoacetic acid derivative (II)
Can be regarded as the end point of the reaction when no is detected from the reaction system.

After completion of the reaction, an acetylenedicarboxylic acid ester represented by the general formula [I] is obtained by usual post-treatments such as solvent evaporation, washing, extraction and concentration, and can be purified by distillation under reduced pressure.

<Effect of the Invention> According to the method of the present invention, the acetylenedicarboxylic acid ester represented by the general formula [I] can be produced by a novel method and industrially advantageously.

The acetylene dicarboxylic acid ester [I]
Can be used as an intermediate in the synthesis of 4-hydroxycyclopentenones [V] by the route shown in the following reaction formula. The 4-hydroxycyclopentenones [V] are useful as intermediates for drugs, particularly prostaglandins (J. Med. Chem., Vol. 26 (1983) p.7).
86).

(In the formula, R represents the same meaning as described above, and * represents an asymmetric carbon atom.) <Examples> Hereinafter, the present invention will be described in more detail with reference to Examples.

Example 1 796 g of toluene was added to 200 g (1.63 mol) of 1,4-dichloro-2-butyne. 568 g of methyl acetoacetate (4.
A mixture of 89 mol) and 896 g (4.65 mol) of a 28% sodium methylate / methanol solution was added at room temperature. The reaction temperature was adjusted to 60 ° C., and the mixture was stirred for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to remove methanol, and then 1.5 l of water and
Was added and stirred. After removing the aqueous layer, the toluene layer was further washed with 1.5 l of water. Thereafter, the toluene layer was concentrated under reduced pressure and then distilled under reduced pressure to obtain 109.7 g (content: 95.8%) of dimethyl 4-octinedioic acid.

Example 2 1258 g (6.52 mol) of a 28% sodium methylate / methanol solution was added to 757 g (6.52 mol) of methyl acetoacetate, and the mixture was cooled to room temperature. In it, 1,4-dichloro-2-
200 g (1.63 mol) of butyne were added. Then raise the reaction temperature to 60
C. and stirred for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to remove methanol, and 2 l of water and toluene 1 were added thereto and stirred. After removing the water bath, the toluene layer was further washed with 2 l of water. Thereafter, the toluene layer was concentrated under reduced pressure, and further distilled under reduced pressure to obtain 96.4 g (content: 93.7%) of dimethyl 4-octynedioic acid.

Example 3 To 200 g (1.63 mol) of 1,4-dichloro-2-butyne was added 796 g of toluene. 568 g of methyl acetoacetate (4.
A mixture of 89 mol) and 942 g (4.89 mol) of a 28% sodium methylate / methanol solution was added at room temperature. When the reaction temperature was 64 ° C. and the mixture was stirred for 9 hours, 94.2 g (0.489 mol) of a 28% sodium methylate / methanol solution was further added. Thereafter, the mixture was stirred at 64 ° C. for 6 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to remove methanol, and 1.5 l of water and toluene 1 were added thereto and stirred. After removing the aqueous layer, add
The toluene layer was washed with 1.5 l. Thereafter, the toluene layer was concentrated under reduced pressure and further distilled under reduced pressure to obtain 117.3 g (content: 96.3%) of dimethyl 4-octynedioic acid.

Example 4 144.5 g (1.245 mol) of methyl acetoacetate, 67.7 g (0.550 mol) of 1,4-dichloro-2-butyne and 500 g of toluene
Was placed in a flask and heated to 80 ° C. 100 g of potassium carbonate was added thereto, and the mixture was stirred at 80 ° C. for 1.5 hours. Thereafter, 104 g of potassium carbonate was further added, and the mixture was stirred at 80 ° C. for 8 hours. Further, 21.5 g (0.185 mol) of methyl acetoacetate and 51.1 g of potassium carbonate were added, and the mixture was stirred and reacted for 4 hours. After the completion of the reaction, salts in the reaction mixture are removed by filtration, and then the reaction mixture is separated.
The mixture was neutralized with 10% hydrochloric acid, washed with water, neutralized under reduced pressure with 10% hydrochloric acid, further washed with water, and concentrated under reduced pressure. The concentrate is distilled under reduced pressure to give 3,8-dimethoxycarbonyl-
44.4 g (content: 84.3%) of 5-decyne-2,9-dione was obtained.

bp 168-172 ° C. Example 5 3,8-Dimethoxycarbonyl-5 obtained in Example 4
-11.7 g of decyne-2,9-dione (content: 84.3%) and 60 g of toluene were placed in a flask, and 60 g of a 28% sodium methylate / methanol solution was added thereto, and the mixture was heated to 70 to 73 ° C and reacted for 13 hours. After the completion of the reaction, the reaction solution was concentrated under reduced pressure, 100 g of toluene and 100 g of water were added, the mixture was shaken, and the toluene layer was separated. The toluene layer was washed with 100 g of water and then concentrated under reduced pressure. The concentrate is distilled under reduced pressure,
2.89 g of dimethyl 4-octinedioic acid (content: 94.5
%).

Reference Example 1,6-dimethoxycarbonyl-3-hexyl (content 83.9
%) 20.0 g (0.0847 mol) is dissolved in methanol 40 g and 5 ° C
Cooled down. Among them, anhydrous barium hydroxide (2N) 33.9
g was added and stirred. After 17 hours, the reaction solution was filtered and dried under reduced pressure, and 18.4 g of the crystals were suspended in 100 g of 1,2-dichloroethane, and 10
% HC 16g water 50g was added and stirred at 40-45 ° C for 2 hours to separate. The organic layer was washed with 50 g of water and concentrated under reduced pressure to obtain 12.5 g of 6-methoxycarbonyl-1-carboxy-3-hexyne. (Yield: 80.2%) mp: 71.5-72.0 ° C. Next, 27.6 g (0.15 mol) of 6-methoxycarbonyl-1 carboxy-3-hexyne (IX) obtained here and 30.furan.
To a mixture of 7 g (0.45 mol) and 150 ml of dichloromethane was added 37.8 g (0.18 mol) of trifluoroacetic anhydride at room temperature and reacted at 30 to 35 ° C. for 24 hours.

After completion of the reaction, the reaction solution was poured into ice water and neutralized with 20% aqueous NaOH. The organic layer was separated and further washed with 5% aqueous sodium bicarbonate and water. The organic layer was concentrated under reduced pressure to obtain 32.3 g (yield 92%) of 1-oxo-1-furyl-6-methoxycarbonyl-4-heptin (VIII). ▲ n ²⁵ _D ▼ 1.5
Next, 2.46 g of sodium borohydride was added to a mixed solution of 30.4 g (0.13 mol) of (VIII) obtained above, 150 ml of methanol and 1.5 g of a 28% sodium methylate / methanol solution.
(0.065 mol) at 5 ° C. 3 hours at the same temperature,
The reaction was further performed at 10 to 15 ° C for 2 hours.

After completion of the reaction, the reaction solution was poured into ice water and extracted with toluene. The organic layer was separated, washed with water, and concentrated to give 29.2 g of 1-hydroxy-1-furyl-6-methoxycarbonyl-4-heptin (VII) (yield 95).
%).

▲ n ²⁵ _D ▼ 1.5082 28.3 g (0.12 mol) of (VII) obtained here, water 1200
g, 1.5 g of acetic acid, and adjust the pH to 4.4 with 5% aqueous NaOH.
The mixture was heated and stirred at 100 ° C. for 25 hours. After completion of the reaction, the reaction solution was cooled and extracted twice with 300 ml of methyl isobutyl ketone.
Separation and concentration of 4-hydroxy-2- (6-
A mixture of methoxycarbonyl-3-hexynyl) -2-cyclopentenone (IV) and 3-hydroxy-2- (6-methoxycarbonyl-3-hexynyl) -2-cyclopentenone (VI) (composition ratio 6: 4 21.5 g (76% yield).

Next, 9.45 g (0.04 g) of the mixture of (IV) and (VI) obtained here
Mol), acetic acid 14g, acetic anhydride 4g and sodium acetate 0.2
g of the mixture was reacted at 115-120 ° C. for 4 hours. The reaction solution was checked by gas chromatography, and after confirming that no reaction raw material was detected in the reaction solution, the reaction was terminated. The reaction solution was concentrated under reduced pressure, and toluene
l and 50 ml of water were added, and the mixture was separated to obtain an organic layer. The organic layer was washed with 8% sodium bicarbonate water, and further washed with water. The obtained organic layer was dried over anhydrous magnesium sulfate, concentrated, and concentrated.
10.5 g of acetoxy-2- (6-methoxycarbonyl-3-hexynyl) -2-cyclopentenone (III) (yield 9
4.5%).

bp 170-175 ° C / 0.5-0.6 mmHg 4-acetoxy-2- (6-methoxycarbonyl-3-hexynyl) -2-cyclopentenone (III) 4.17 g obtained above, dichloromethane 2 ml, Arthrobacter lipase A flask was charged with 60 mg (manufactured by Shin Nippon Chemical) and 50 ml of 0.2 molar phosphate buffer (pH 7.5).
Stir vigorously at 0 ° C. for 15 hours.

After completion of the reaction, the reaction solution was extracted twice with 40 ml of methyl isobutyl ketone, and the organic layers were combined and concentrated under reduced pressure to obtain 4.02 g of a concentrated residue.

The concentrated residue was purified by column chromatography using toluene: ethyl acetate (5: 3) to give 4R (+)-hydroxy-2- (6
-Methoxycarbonyl-3-hexynyl) -2-cyclopentenone 1.24 g ▲ [α] ²⁰ _D ▼ + 18.1 ° (c = 1, CHCl ₃ ) 97.8% ee and 4S (−)-acetoxy-2- (6 -Methoxycarbonyl-3-hexynyl) -2-cyclopentenone 2.59
g was obtained.

▲ [α] ²⁰ _D ▼ -29.2 ° (c = 1, CHCl ₃ ) Then, 4R (+)-hydroxy-2- (6-methoxycarbonyl-3-hexynyl) -2-cyclopentenone 1.18 obtained here g, Rindora - catalyst _{(5% Pd-CaCO 3 -PbO} ) 60
mg, 0.5 g of hexene and 30 ml of toluene were charged into a normal-pressure hydrogenation apparatus and reduced at room temperature under normal pressure. The reaction was completed in one hour. After completion of the reaction, the catalyst was removed by filtration, and after concentration, the residue was purified by a silica gel column to give 4R (+)-hydroxy-2- (6-methoxycarbonyl-3-cis-
1.14 g of (hexenyl) -2-cyclopentenone were obtained.
(Yield 96%) ▲ [α] ²⁰ _D ▼ + 19.4 ° (c = 1, CHCl ₃ ) 97.8% ee

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI // C07B 61/00 300 C07B 61/00 300 (72) Inventor Sachiko 2-10-1 Tsukahara, Takatsuki-shi, Osaka Sumitomo Chemical (72) Inventor Masayoshi Minami 2-10-1, Tsukahara, Takatsuki-shi, Osaka Sumitomo Chemical Industries, Ltd. (56) References JP-A-60-112834 (JP, A) JP-A-62-106041 (JP, A) Didier VILLEMIN et al. , Tetrahedron Letters, Vol. 23, No. 49, p. 5139-5140 (58) Field surveyed (Int. Cl. ⁶ , DB name) C07C 69/606 C07C 69/738 C07C 67/317 C07C 67/343 CA (STN) REGISTRY (STN)

Claims (5)

(57) [Claims] 1. A compound of the general formula [IV] (Wherein X ¹ and X ² each represent a chlorine atom, a bromine atom, an iodine atom, a methanesulfonyloxy group or a p-toluenesulfonyloxy group); and an acetylene derivative represented by the general formula [III]: Wherein R represents a C ₁ -C ₆ alkyl group in the presence of metal alkoxides with an acetoacetic ester represented by the general formula [I]: (Wherein, R represents the same meaning as described above.) A method for producing an acetylenedicarboxylic acid ester represented by the formula: 2. The general formula [II] (Wherein R represents the same meaning as described above). A method for producing an acetylenedicarboxylic acid ester represented by the general formula [I], wherein the acetoacetic acid derivative represented by the following formula is reacted in the presence of a metal alkoxide. 3. An acetoacetic acid derivative represented by the general formula [II] by reacting an acetylene derivative represented by the general formula [IV] with an acetoacetic ester represented by the general formula [III] in the presence of a carbonate. 3. The method according to claim 2, wherein 4. An acetylene derivative represented by the general formula [IV] and an acetoacetate ester represented by the general formula [III] are reacted in the presence of a carbonate to form a compound represented by the general formula [II]: For producing acetoacetic acid derivatives. 5. An acetoacetic acid derivative represented by the general formula [II].