JPWO2013038931A1 - Process for producing 2-oxo-2H-cyclohepta [b] furan analog - Google Patents

Abstract

A method for easily producing a 2-oxo-2H-cyclohepta [b] furan analog useful as a pharmaceutical intermediate in high yield, low cost and high purity, wherein the general formula (I): [R is a hydrogen atom Alternatively, a 2-chlorotropone analog represented by a lower alkyl group which may be branched (1-5 carbon atoms)] and malonic acid dimethyl ester are reacted in an alcohol solvent in the presence of an alkali metal hydroxide. A process for producing a 2-oxo-2H-cyclohepta [b] furan analog represented by the formula (II): [R is as defined above].

Description

  The present invention relates to a process for producing 2-oxo-2H-cyclohepta [b] furan analogs useful as intermediates for pharmaceutical synthesis.

  Traditionally, 2-oxo-2H-cyclohepta [b] furan analogs have been used as intermediates in pharmaceutical synthesis. For example, methyl 5-isopropyl-2-oxo-2H-cyclohepta [b] furan-3-carboxylate represented by the following formula (III) is an intermediate for the production of anti-ulcer agent eguarene sodium (registered trade name Azuroxa) Useful as.

  Several methods for producing 2-oxo-2H-cyclohepta [b] furan analogs from 2-chlorotropone analogs have been proposed to date. For example, as shown in Scheme 1, 2-chloro-5-isopropyltropone (IV) and malonic acid diethyl ester are reacted in the presence of sodium ethoxide in an ethanol solvent to give ethyl 5-isopropyl-2-oxo- 2H-cyclohepta [b] furan-3-carboxylate (V) is produced (Non-patent Document 1). This reaction is difficult to handle because it uses sodium ethoxide which is sensitive to moisture.

  Further, as shown in Scheme 2, 2-chloro-5-isopropyltropone (IV) and malonic acid diester ester are reacted in the presence of t-butylamine or sodium alkoxide to give methyl 5-isopropyl-2-oxo-2H. -Cyclohepta [b] furan-3-carboxylate (V) is synthesized to produce an azulene derivative (VI) (Non-patent Document 2, Patent Document 1). For this reaction, an expensive compound such as t-butylamine is used.

  Therefore, t-butylamine and sodium alkoxide for reacting 2-chloro-5-isopropyl tropone and malonic acid diester ester to obtain 2-oxo-2H-cyclohepta [b] furan analogues inexpensively and efficiently. The discovery of an alternative compound is desired.

JP-A-3-193743

Chemical Abstracts, 54, 10509a, 1960 Tetrahedron, 27, 3359, 1971

  The present invention reacts 2-chlorotropone analog and malonic acid dimethyl ester to produce 2-oxo-2H-cyclohepta [b] furan analog, which is an inexpensive alternative to the above-mentioned t-butylamine or sodium alkoxide. An object of the present invention is to provide a compound that is easy to handle and can be produced with high yield and high purity.

  As a result of intensive studies to solve the above-mentioned problems, the present inventor conducted a reaction between 2-chlorotropone analog and malonic acid dimethyl ester in an alcohol solvent, particularly an alkali metal hydroxide, particularly sodium hydroxide or hydroxide. It has been found that by performing in the presence of potassium, the reaction proceeds smoothly under mild conditions and 2-oxo-2H-cyclohepta [b] furan analog (II) can be produced in high yield and high purity. The present invention has been completed.

  That is, the present invention relates to the general formula (I):

〔式中、Rは水素原子あるいは分岐してもよい低級アルキル基（炭素数1−5）を示す〕
で示される2-クロロトロポン類縁体とマロン酸ジメチルエステルを、アルコール溶媒中、アルカリ金属水酸化物の存在下で反応させることを特徴とする、一般式（II）：

[Wherein R represents a hydrogen atom or a lower alkyl group which may be branched (1-5 carbon atoms)]
A compound represented by the general formula (II), wherein the 2-chlorotropone analog represented by formula (II) and dimethyl malonate are reacted in an alcohol solvent in the presence of an alkali metal hydroxide:

（式中、Rは前述と同義である）
で示される2-オキソ-2H-シクロヘプタ[b]フラン類縁体の製造方法である。

(Wherein R is as defined above)
Is a method for producing 2-oxo-2H-cyclohepta [b] furan analog represented by the formula:

  The alkali metal hydroxide is preferably sodium hydroxide or potassium hydroxide. The alcohol solvent is preferably methanol. In the above reaction, it is preferable to use 0.5 to 3.0 moles of malonic acid dimethyl ester and alkali metal hydroxide with respect to 1 mole of 2-chlorotropone analog (I).

  In the present invention, the 2-chlorotropone analog and malonic acid dimethyl ester are reacted to produce 2-oxo-2H-cyclohepta [b] furan analog. In addition, it can be produced with high purity. In addition, since alkali metal hydroxides are inexpensive and easy to handle, 2-oxo-2H-cyclohepta [b] furan analogs can be easily produced at low cost. That is, according to the present invention, a 2-oxo-2H-cyclohepta [b] furan analog useful as a pharmaceutical intermediate can be easily obtained in high yield, low cost and high purity.

  In the compounds represented by the above general formula (I) and general formula (II), R is a hydrogen atom or a lower alkyl group (1-5 carbon atoms) which may be branched. Here, the lower alkyl group which may be branched is, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group, a butyl group, an isobutyl group, a pentyl group or a cyclopentyl group. The 2-chlorotropone analog represented by the general formula (I) of the starting material can be produced by a known method (for example, Journal of American Chemical Society, 74, 5683, 1952, Journal of Organic Chemistry, 43, 3621, 1978, Patent Document 1).

  Scheme 3 shows a method for producing 2-oxo-2H-cyclohepta [b] furan represented by the general formula (II) from the 2-chlorotropone analog represented by the general formula (I) in the present invention.

  In this reaction, it is preferable to use 0.5 to 3.0 moles of malonic acid dimethyl ester and alkali metal hydroxide, respectively, more preferably 1 mole per 2-chlorotropone analog (I). The range is 8 to 2.2 mol. Examples of the alkali metal hydroxide include lithium hydroxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide, and cesium hydroxide, with sodium hydroxide and potassium hydroxide being preferred. As the reaction solvent, alcohols such as methanol, ethanol, 1-propanol and isopropanol are used, preferably methanol. The reaction is carried out at -78 ° C to the solvent reflux temperature, and the preferred reaction temperature is in the range of -30 ° C to 10 ° C.

  The present invention will be described with reference to examples. The example shows the reaction of 2-chloro-5-isopropyltropone (IV) with malonic acid diester ester to give methyl 5-isopropyl-2-oxo-2H-cyclohepta [b] furan-3-carboxylate (III ).

Examples using t-butylamine and sodium methoxide, which have been conventionally used, are listed as Comparative Examples 1 and 2. The following abbreviations were used for the description of proton nuclear magnetic resonance spectrum ( ¹ H-NMR) data. That is, s is a singlet, d is a doublet, t is a triplet, q is a quartet, m is a multiplet, and b is broad. The HPLC purity was measured under the conditions of column: Inertsil ODS-2 (GL Sciences Inc.), moving bed: acetonitrile / water = 1/1 (v / v), measurement wavelength: 210 nm.

Example 1
To a solution of 2-chloro-5-isopropyltropone (1.494 g) and dimethyl malonate (1.9 mL) in methanol (5.0 mL), add a solution of sodium hydroxide (0.656 g) in methanol (7.0 mL) to -19 to -6. After dropwise addition at ° C, the mixture was stirred for 1 hour. The reaction solution was poured into water and stirred at room temperature. The solid was collected by filtration, washed with water, and dried to give methyl 5-isopropyl-2-oxo-2H-cyclohepta [b] furan-3-carboxylate (1.726 g) as a yellow solid. The molar ratio of 2-chloro-5-isopropyl tropone, dimethyl malonate and sodium hydroxide is 1: 2: 2. The yield was 85.6%. The HPLC purity was 99.3%.
¹ H-NMR (CDCl ₃ ) δ = 1.36 (d, J = 7Hz, 6H), 3.05-3.11 (m, 1H), 3.94 (s, 3H), 7.26-7.30 (m, 1H), 7.37-7.48 ( m, 2H), 88.90 (d, J = 2Hz, 1H).

Example 2
After dropwise addition of a solution of potassium hydroxide (0.184 g) in methanol (2.0 mL) to a solution of 2-chloro-5-isopropyltropone (0.300 g) and dimethyl malonate (0.37 mL) in methanol (1.6 mL) with ice cooling And stirred for 2 hours. The reaction solution was poured into water and stirred at room temperature. The solid was collected by filtration, washed with water, and dried to give methyl 5-isopropyl-2-oxo-2H-cyclohepta [b] furan-3-carboxylate (0.353 g) as a yellow solid. The molar ratio of 2-chloro-5-isopropyl tropone, dimethyl malonate and potassium hydroxide is 1: 2: 2. The yield was 87.4%. The HPLC purity was 98.5%.
¹ H-NMR (CDCl ₃ ) δ = 1.36 (d, J = 7Hz, 6H), 3.05-3.11 (m, 1H), 3.94 (s, 3H), 7.26-7.30 (m, 1H), 7.37-7.48 ( m, 2H), 8.90 (d, J = 2Hz, 1H).

Comparative Example 1
To a solution of 2-chloro-5-isopropyltropone (3.009 g) and dimethyl malonate (3.7 mL) in methanol (24.0 mL), t-butylamine (3.4 mL) was added dropwise at −14 to −5 ° C. After stirring at -16 to -9 ° C for 1 hour, the mixture was stirred at -7 to 29 ° C for 1 hour. The reaction solution was poured into water. The solid was collected by filtration, washed with water, and dried to give methyl 5-isopropyl-2-oxo-2H-cyclohepta [b] furan-3-carboxylate (3.234 g) as a yellow solid. The molar ratio of 2-chloro-5-isopropyl tropone, dimethyl malonate and t-butylamine is 1: 2: 2. The yield was 79.6%. The HPLC purity was 93.9%.
¹ H-NMR (CDCl ₃ ) δ = 1.36 (d, J = 7Hz, 6H), 3.05-3.11 (m, 1H), 3.94 (s, 3H), 7.26-7.30 (m, 1H), 7.37-7.48 ( m, 2H), 88.90 (d, J = 2Hz, 1H).

Comparative Example 2
Process for producing methyl 5-isopropyl-2-oxo-2H-cyclohepta [b] furan-3-carboxylate
A solution of sodium methoxide in methanol (3.6 mL) in 2-chloro-5-isopropyltropone (0.300 g) and dimethyl malonate (0.37 mL) in methanol (prepared from 0.075 g sodium and 2.0 mL methanol) on ice. After dropwise addition under cooling, the mixture was stirred for 2 hours. The reaction solution was poured into water. The solid was collected by filtration, washed with water, and dried to give methyl 5-isopropyl-2-oxo-2H-cyclohepta [b] furan-3-carboxylate (0.343 g) as a yellow solid. The molar ratio of 2-chloro-5-isopropyl tropone, dimethyl malonate and sodium methoxide is 1: 2: 2. The yield was 84.9%. The HPLC purity was 98.2%.
¹ H-NMR (CDCl ₃ ) δ = 1.36 (d, J = 7Hz, 6H), 3.05-3.11 (m, 1H), 3.94 (s, 3H), 7.26-7.30 (m, 1H), 7.37-7.48 ( m, 2H), 88.90 (d, J = 2Hz, 1H).
The yield and purity of the target compounds obtained in Examples and Comparative Examples are summarized in Table 1.

  According to Table 1, what used the sodium hydroxide of Example 1 of this invention and the potassium hydroxide of Example 2 than the thing using the t-butylamine of the comparative example 1, and the sodium methoxide of the comparative example 2 It can also be seen that the pure yield (yield × HPLC purity) of the target compound is excellent. In addition, sodium hydroxide and potassium hydroxide are inexpensive and easy to handle, and thus have an advantage of easy synthesis.

Claims (4)

Formula (I):

[Wherein, R represents a hydrogen atom or a lower alkyl group which may be branched (1-5 carbon atoms)]
A compound represented by the general formula (II), wherein the 2-chlorotropone analog represented by formula (II) and dimethyl malonate are reacted in an alcohol solvent in the presence of an alkali metal hydroxide:

(Wherein R is as defined above)
A process for producing a 2-oxo-2H-cyclohepta [b] furan analog represented by the formula:   The method for producing a 2-oxo-2H-cyclohepta [b] furan analog according to claim 1, wherein the alkali metal hydroxide is sodium hydroxide or potassium hydroxide.   The method for producing a 2-oxo-2H-cyclohepta [b] furan analog according to claim 1, wherein the alcohol solvent is methanol.   The 2-oxo-2H-cyclohepta according to any one of claims 1 to 3, wherein 0.5 to 3.0 moles of malonic acid dimethyl ester and alkali metal hydroxide are used per 1 mole of 2-chlorotropone analog (I), respectively. b] A method for producing furan analogues.