KR100395231B1 - Novel process for preparing methyl 7-(3-hydroxy-5-oxo-1-cyclopenten-1-yl)heptanoate - Google Patents

Abstract

The present invention provides a methyl 8-hydroxyoctanoate of the formula (5) by (a) selectively reducing the suveric acid monomethyl ester of the formula (4) in the presence of a reducing agent in a solvent, and (b) a compound of the formula (5) Methyl 8-oxooctanoate of the following Chemical Formula 6 was prepared by oxidation in a solvent, and (c) a furan group was introduced into the compound of Chemical Formula 6 using a Grinard reaction to obtain a methyl 8- (2-furanyl) -8-hydroxyoctanoate is prepared, and (d) methyl 7- (2-hydroxy-5-oxo of formula (8) is reacted by chemical reaction of compound of formula (7) in solvent under weakly acidic conditions -3-cyclopenten-l-yl) heptanoate is prepared, and then (e) reacting the compound of formula 8 in a solvent in the presence of a chloral and organic amine catalyst to prepare a compound of formula 1 It is about.

Description

New process for preparing methyl 7- (3-hydroxy-5-oxo-1-cyclopenten-l-yl) heptanoate {Novel process for preparing methyl 7- (3-hydroxy-5-oxo-1-cyclopenten- 1-yl) heptanoate}

The present invention relates to a novel process for preparing methyl 7- (3-hydroxy-5-oxo-1-cyclopenten-l-yl) heptanoate represented by the following general formula (1):

[Formula 1]

Compounds of formula (I) according to the invention are known from the literature (USP 3,965,143, Journal of Medicinal Chemistry, Vol. 20, No. 9, 1152-1159, 1977) as the most important intermediates in the synthesis of prostaglandin E ₁ derivatives.

Since prostaglandin E ₁ has a very strong and diverse biological activity, many efforts have been made to develop an effective method of synthesis in the chemical and chemical fields, and many derivatives have been synthesized in the process. Prostaglandin E ₁ derivatives that are currently developed as pharmaceuticals include misoprostol and alprostadil of formulas (2) and (3), which are used as effective gastric ulcer therapeutic agents and heart failure therapeutic agents. .

The development of a convenient and useful synthesis of prostaglandin E ₁ derivatives with such potent physiological activity is not only applicable to the synthesis of various related drugs but also directly applicable to the synthesis of many other prostaglandins in nature. It's very big.

Synthesis of methyl 7- (3-hydroxy-5-oxo-1-cyclopenten-1-yl) heptanoate used as an important intermediate of prostaglandin E ₁ derivatives is reported in US Pat. No. 3,965,143 (1976). The method of following Reaction Scheme 1 which exists is mentioned.

However, it has been recognized that the above method has the following problems.

That is, there are many synthesis steps from the starting material to the synthesis of the desired methyl 7- (3-hydroxy-5-oxo-1-cyclopenten-1-yl) heptanoate, and thus the reaction yield is very low, resulting in mass production. Not suitable for use That is, in the method of Scheme 1, the target material is manufactured through a total of eight steps. Particularly, in steps 2 and 4, strict anhydrous conditions are required, and there is a difficulty in exposing reagents such as MeMgBr and Kt-BuO to the air. In 4, the side reactions are so severe that the yield of the reaction is very low due to the difficulty in separating the target substance.

On the other hand, methyl 7- (3-hydroxy-5-oxo-1-cyclopenten-l-yl) heptanoate, which is the object of the present invention, is not prepared, but methyl 7- (3- Methods for preparing hydroxy-5-oxo-1-cyclopenten-l-yl) -4 (Z) -heptenoate are described in Journal of Organic Chemistry, Vol. 56, No. 7, 2549-2552. , 1991).

Thus, the present inventors conducted an intensive study to develop a method for preparing a compound of Formula 1 according to the present invention more economically by solving the problems of the prior art as described above. Using the manufacturing method consisting of five steps as described below using a suberic acid monomethyl ester) as a starting material was found that this object can be achieved and completed the present invention. That is, according to the production method of the present invention, it is possible to mass-produce the compound of Formula 1 in a safe, economical and high yield, thereby providing a useful medicine at a significantly lower price.

The present invention provides a methyl 8-hydroxyoctanoate of the formula (5) by (a) selectively reducing the suveric acid monomethyl ester of the formula (4) in the presence of a reducing agent in a solvent, and (b) a compound of the formula (5) Methyl 8-oxooctanoate of the following Chemical Formula 6 was prepared by oxidation in a solvent, and (c) a furan group was introduced into the compound of Chemical Formula 6 using a Grinard reaction to obtain a methyl 8- (2-furanyl) -8-hydroxyoctanoate is prepared, and (d) methyl 7- (2-hydroxy-5-oxo of formula (8) is reacted by chemical reaction of compound of formula (7) in solvent under weakly acidic conditions -3-cyclopenten-l-yl) heptanoate is prepared, and then (e) reacting the compound of formula 8 in a solvent in the presence of a chloral and organic amine catalyst to prepare a compound of formula 1 It is about.

[Formula 4]

[Formula 5]

[Formula 6]

[Formula 7]

[Formula 8]

Representation of the production method according to the present invention is shown in Scheme 2.

Each step is described in more detail as follows.

In order to prepare the compound of Formula 5 in step (a), only the carboxylic acid group except for the ester group in the submersible monomethyl ester of Formula 4 should be selectively reduced. In general, when the acid and the ester coexist, it is not easy to selectively reduce only the acid portion to alcohol, and the types of reducing agents that can be used for this purpose are very limited. For example, sodium borohydride [NaBH ₄ ] -iodine [I ₂ ], BH ₃ -tetrahydrofuran [THF], NaBH ₄ -catechol, NaBH ₄ -CF ₃ COOH, NaBH ₄ -HCl, NaBH ₄ -H ₂ SO ₄ or the like can be used. Among them, sodium borohydride and iodine can be particularly preferably used as reducing agents, sodium borohydride is 1.08 to 1.32 equivalent times of the compound of formula 4, iodine 0.45 to 0.55 equivalent times, preferably sodium bo 1.2 equivalents of lohydride and 0.5 equivalents of iodine are used. In the reaction, at least one selected from tetrahydrofuran, toluene and benzene may be used, and preferably tetrahydrofuran is used.

In step (b) the methyl 8-hydroxyoctanoate of formula 5 obtained in step (a) is oxidized to the aldehyde compound of formula 6 in the presence of an oxidizing agent in a solvent. As the oxidizing agent, at least one selected from pyridinium chlorochromate, pyridinium dichromate, pyridinium dichromate, oxalylchloride and methyl sulfoxide may be 1.1 to 1.5 equivalents based on the compound of Formula 5. It is used in the range, dichloromethane or dichloroethane is used as the solvent. Preferably, a compound of the formula (5) diluted in dichloromethane is added to a mixture of pyridinium chloro chromate and celite to obtain a target compound. In this case, celite may be used together with the oxidizing agent, and the use of celite is advantageous because it lowers the viscosity of the tar-like material produced after the reaction, thereby facilitating purification of the reaction product.

In step (c), furanyl is introduced into methyl 8-oxooctanoate of formula (6) by using a Grignard reaction to obtain the furanyl compound of formula (7). The Grignard reaction uses a Grignard reagent generated in situ using n-butyllithium and Mg (II) salts, preferably MgCl ₂ or MgBr ₂ . As the solvent, one or more selected from tetrahydrofuran and diethyl ether is used. The reaction proceeds by dissolving furan in a solvent, cooling it to -15 to -8 ° C, adding n-butyllithium (n-BuLi) dropwise thereto, and then raising the temperature to 0 ° C and stirring for 20 to 45 minutes, followed by anhydrous Mg (II) salt is added, and the temperature of the reaction solution is adjusted to -35 to 20 ° C, and then the compound of Formula 6 is added. Preferably, the dropwise addition of n-BuLi is performed at −10 ° C., MgCl ₂ is added, followed by stirring at 20 ° C. for 100 minutes, and the aldehyde compound of Chemical Formula 6 may obtain the best results when added dropwise at −25 ° C. FIG. The yield of the reaction is determined by the purity of n-BuLi (hexane solution), and commercially available 1.3M, 1.6M and 2.5M solutions can be used. In addition, a pentane solution can also be used. Methyl 8- (2-furanyl) -8-hydroxyoctanoate of Formula 7 thus obtained can be separated and purified in a general manner and can be used for the next reaction without further purification.

In step (d), the compound of formula (7) obtained in step (c) is subjected to electroreaction in a solvent under weakly acidic conditions to give methyl 7- (2-hydroxy-5-oxo-3-cyclopenten-l-yl) of formula (8). Convert to heptanoate. The acidity of the reaction solution is preferably adjusted to a pH range of 3.5 to 6, and a solvent such as an acidic phosphate buffer solution (pH 3.5) or a pH 3.5 to 6 range or a mixture of water and an organic solvent in the same pH range may be used. have. The organic solvent which can be mixed with water is at least one selected from dioxane, tetrahydrofuran, diethyl ether, ethylene glycol, ethyl acetate, acetic acid, toluene, dichloromethane, dichloroethane, dimethylformamide and dimethyl sulfoxide. The water and the organic solvent may be used by mixing in a volume ratio of 1: 1.5 to 1: 1.6. The best results are obtained when a mixture of water and dioxane is used as the solvent. This potential reaction can also be carried out without a catalyst, but a catalyst can be used to increase the reaction rate. Catalysts include metal salts, such as chloride, bromide, sulfate or oxide salts of Na, K, Zn, Ca, Mg, Co or Al; Organic quaternary ammonium salts such as tetrabutylammonium bromide; Sulfurants, for example higher aliphatic salts such as polyoxyethylene alkylphenol ethers, are suitable, preferably from 1/200 to 5 times by weight based on the compound of formula (7). The reaction temperature is appropriately maintained at 20 to 160 ℃, when using a mixed solution of dioxane and water as a solvent, the best results were obtained by performing the reaction at 100 ℃, the reflux temperature of the mixture. The reaction time is preferably about 18 to 22 hours. If the reaction time is longer than 22 hours, since the liquidity of the reaction liquid is acidic, side reactions increase, such as hydrolysis of the ester moiety to an acid, leading to a decrease in yield. If the reaction time is less than 18 hours, the reaction is not sufficiently performed. Because you can't. The best results were obtained when the reaction time was 20 hours. If the ester moiety is hydrolyzed during the reaction to produce a large amount of acid as a by-product, the reaction product can be converted back to the ester by reacting with potassium carbonate and methane iodide in acetone solvent. However, this additional reaction may be omitted if the amount of acid obtained as a by-product during the potential reaction is small.

In step (e), the compound of formula (8) obtained in step (d) is subjected to a potential reaction in the presence of a chloral and organic amine catalyst in a solvent to obtain a compound of formula (1). In this reaction, the liquidity of the reaction solution is suitably about pH 6-9, and preferably at pH 7-9, the best results can be obtained. Chloral is an anhydrous one, and 0.005 to 1 equivalent times, preferably 0.05 to 1 equivalent times, based on the compound of the formula (8). As the organic amine catalyst, one or more selected from triethylamine, N-methylmorpholine, pyridine and lutidine can be used, and among these, triethylamine can be used to obtain the best results. The organic amine uses 0.005 to 0.8 equivalent times with respect to the compound of formula 8, and the best results are obtained when 0.65 equivalent times. In the reaction (e), at least one selected from toluene, diethyl ether, benzene, acetone, ethyl acetate, heptane and cyclohexane may be used as the solvent. In addition, the reaction is carried out at a temperature of 0 to 90 ℃, especially when toluene is used as the solvent is most preferably carried out at 65 ℃.

The compound of formula 1 obtained through the above-described method can be separated and purified using conventional methods such as extraction, recrystallization or column chromatography.

When the compound of Formula 1 is prepared according to the method of the present invention, the target compound of Chemical Formula 1 may be prepared in a high yield of about 40 to 45% by performing 5 steps of reaction from the submersible monomethyl ester. Can be. This degree of yield is significantly improved compared to the total yield of 11.5% obtained according to the conventional scheme 1, it can be predicted that the industrial use of the present invention can be used in a very economical and efficient process.

Hereinafter, the present invention will be described in more detail based on the following examples. However, these examples are only for the understanding of the present invention, and the scope of the present invention in any sense is not limited to these examples.

Example 1 Preparation of Methyl 8-hydroxyoctanoate

Sodium borohydride (37.83 g) was suspended in THF (220 mL), submerged monohydroester ester (146 g) dissolved in THF (220 mL) at room temperature was added dropwise, and stirred until H ₂ generation stopped. It was. The reaction solution was cooled to 0 ° C. and iodine (98.4 g) dissolved in THF (220 mL) was added dropwise and stirred for 1.5 hours. After completion of the reaction, 3N-HCl (324 ml) was added to terminate the reaction. The organic layer was separated and the aqueous layer was extracted three times with diethyl ether (100 mL). The combined organic layers were washed twice with 3N-NaOH (300 mL), dried over Na ₂ SO ₄ , filtered and concentrated to give 120.3 g (89% yield) of the title compound. The obtained compound was used for the next reaction without further purification.

¹ H-NMR (500MHz, CDCl ₃ ) δ 1.35 (brs, 6H), 1.54-1.65 (2brt, 4H), 2.30 (t, 2H), 3.63 (t, 2H), 3.68 (s, 3H)

¹³ C-NMR (500MHz, CDCl ₃ ) 25.5, 26.4, 29.4, 29.7, 33.3, 34.7, 52.1, 63.6, 175.0

Example 2: Preparation of Methyl 8-oxooctanoate

The reflux apparatus was dissolved in dichloromethane (1,100 mL) and PCC (pyridinium chlorochromate; 239 g) and Celite 545 (256 g) in one flask. The compound (128 g) obtained in Example 1 at 0 ° C. was diluted in dichloromethane (200 mL), then added dropwise to the solution in the flask and stirred at room temperature for 1.5 hours. After completion of the reaction, diethyl ether (1,500 mL) was added and stirred at room temperature for 1.5 hours. The reaction solution was filtered over Celite (300 g), washed with diethyl ether (500 mL), and concentrated under reduced pressure to give 108.2 g (yield 85%) of the title compound. The obtained compound was used in the next reaction without further purification.

Example 3: Preparation of Methyl 8-Oxooctanoate

The reaction was carried out in the same manner as in Example 2, except that PDC (pyridinium dichlorochromate) was used instead of PCC to give the title compound (yield 83%).

Example 4 Preparation of Methyl 8- (2-furanyl) -8-hydroxyoctanoate

Furan (66.49 mL) was dissolved in anhydrous THF (340 mL) and then cooled to -10 ° C, to which n-BuLi (2.5M in hexane; 234.4 mL) was added dropwise. After stirring at 0 ° C. for 30 minutes, MgCl ₂ (53.51 g) was added all at once and stirred at room temperature for 1.5 hours. The compound (101 g) obtained in Example 2, cooled to -25 DEG C and dissolved in THF (265 mL) was added dropwise and stirred for 25 minutes. After completion of the reaction, saturated NH ₄ Cl aqueous solution was added to the reaction solution to terminate the reaction, and diluted with ethyl acetate (300 mL). The organic layer was separated and the aqueous layer was extracted twice with ethyl acetate (300 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 119.7 g (yield 85%) of the title compound. The obtained compound was used in the next reaction without further purification.

¹ H-NMR (500 MHz, CDCl ₃ ) δ 1.26-1.45 (m, 6H), 1.57-1.63 (m, 2H), 1.78-1.86 (m, 2H), 2.28 (t, 2H), 2.47 (brs, 1H ), 3.63 (s, 3H), 4.64 (brs, 1H), 6.21 (dd, 1H), 6.32 (dd, 1H), 7.35 (dd, 1H)

¹³ C-NMR (500 MHz, CDCl ₃ ) 25.5, 26.0, 29.6, 29.8, 34.7, 36.1, 52.2, 68.3, 106.4, 110.7, 142.4, 157.7, 175.0

Example 5: Preparation of Methyl 7- (2-hydroxy-5-oxo-3-cyclopenten-l-yl) heptanoate

The compound (116.6 g) and ZnCl ₂ (258 g) obtained in Example 4 were added to a mixed solution of dioxane (2.3 L) and water (1.5 L) and heated to reflux for 22 hours. The reaction solution was cooled to room temperature and adjusted to pH 1 with concentrated hydrochloric acid. The reaction solution was extracted three times with ethyl acetate (250 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was dissolved in acetone (5.1 L), and K ₂ CO ₃ (338.6 g) and methane iodide (347.7 g) were added thereto, followed by heating to reflux for 9 hours. After completion of the reaction the reaction solution was filtered over Celite (200g) and concentrated under reduced pressure to give 93.2g (yield 80%) of the title compound.

Example 6: Preparation of Methyl 7- (3-hydroxy-5-oxo-1-cyclopenten-l-yl) heptanoate

The compound (113 g) and triethylamine (31.3 g) obtained in Example 5 were dissolved in toluene (1.6 L), and anhydrous trichloroacetaldehyde (chloro; 4.0 g) was added thereto, followed by warming to 65 ° C. Stir for 6 hours. After completion of the reaction, water (500 mL) was added and extracted three times with diethyl ether (150 mL). The organic layers were combined, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: ethyl acetate / n-hexane = 2/1, v / v) to give 88 g (yield 78%) of the title compound as white crystals.

¹ H-NMR (500 MHz, CDCl ₃ ) δ 1.31-1.35 (m, 4H), 1.46-1.51 (m, 2H), 1.60-1.66 (m, 3H), 2.16-2.20 (m, 3H), 2.28-2.32 (m, 3H), 2.80 (dd, 1H), 3.66 (s, 3H), 4.95 (m, 1H), 7.15 (m, 1H)

¹³ C-NMR (500 MHz, CDCl ₃ ) 24.3, 24.7, 27.1, 28.7, 28.8, 34.0, 44.9, 51.5, 68.5, 148.0, 155.7, 174.3, 206.1

Melting point: 50-51 ℃

Claims (14)

(a) Substituting Submeric Acid Monomethyl Ester of Formula 4, optionally in the presence of a reducing agent in a solvent to prepare methyl 8-hydroxyoctanoate of Formula 5, and (b) Oxidizing the compound of Formula 5 in solvent To prepare a methyl 8-oxooctanoate of the formula (6), and (c) by introducing a furan group to the compound of the formula (6) using the Grinard reaction to the methyl 8- (2- Furanyl) -8-hydroxyoctanoate is prepared, and (d) the compound of formula 7 is subjected to a potential reaction in a solvent under mildly acidic conditions to methyl 7- (2-hydroxy-5-oxo-3- Preparing cyclopenten-l-yl) heptanoate, and then (e) reacting the compound of formula 8 in a solvent in the presence of a chloral and an organic amine catalyst to prepare a compound of formula 1 Way: [Formula 4] [Formula 5] [Formula 6] [Formula 7] [Formula 8] [Formula 1] The process of claim 1 wherein the reducing agent in step (a) is sodium borohydride [NaBH ₄ ] -iodine [I ₂ ], BH ₃ -tetrahydrofuran [THF], NaBH ₄ -catechol, NaBH ₄ -CF ₃ COOH, NaBH ₄ -HCl or NaBH ₄ -H ₂ SO ₄ . The process of claim 1 wherein the solvent in step (a) is at least one selected from tetrahydrofuran, toluene and benzene. The method of claim 1, wherein at least one selected from pyridinium chloro chromate, pyridinium dichromate, oxalyl chloride, and methyl sulfoxide in step (b). Using an oxidizing agent in the range of 1.1 to 1.5 equivalent times relative to the compound of formula 5. The process according to claim 1, wherein n-butyllithium and Mg (II) salts are 1.3 M, 1.6 M or 2.5 M hexane solution for the Grignard reaction in step (c). The process of claim 1 wherein the solvent in step (c) is tetrahydrofuran or diethyl ether. The method of claim 1, wherein the acidity of the reaction solution in step (d) is adjusted to a pH of 3.5 to 6 range. The method of claim 1, wherein in step (d), a solvent having a pH of 3.5 to 6 or a mixture of water and an organic solvent is used as the solvent. The method of claim 8, wherein the buffer is acidic phosphate buffer (pH 3.5), the organic solvent is dioxane, tetrahydrofuran, diethyl ether, ethylene glycol, ethyl acetate, acetic acid, toluene, dichloromethane, dichloroethane, dimethylformamide And dimethyl sulfoxide, wherein the mixing ratio of water and organic solvent is 1: 1.5 to 1: 1.6 by volume. The process according to claim 1, further comprising: a chloride, bromide, sulfate or oxide salt of Na, K, Zn, Ca, Mg, Co or Al in step (d); Organic quaternary ammonium salts; And at least 1/200 to 5 weight times of the at least one catalyst selected from the surfactants based on the compound of formula (7). The process according to claim 1, wherein the reaction product obtained in step (d) is reacted with potassium carbonate and methane iodide in acetone solvent before use in step (e). The method of claim 1, wherein in step (e) anhydrous chloral is used in an amount of 0.005 to 1 equivalent times based on the compound of formula 8. The process according to claim 1, wherein in step (e) at least one organic amine selected from triethylamine, N-methylmorpholine, pyridine and lutidine is used in an amount of 0.005 to 0.8 equivalent times with respect to the compound of formula (8). The process of claim 1 wherein the solvent in step (e) is at least one selected from toluene, diethyl ether, benzene, acetone, ethyl acetate, heptane and cyclohexane.